Cycloalkyl inhibitors of potassium channel function

ABSTRACT

Novel cycloalkyl compounds useful as inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K +  channels, especially inhibitors K v 1.5 which has been linked to the ultra-rapidly activating delayed rectifier K +  current I Kur ), methods of using such compounds in the prevention and treatment of arrhythmia and I Kur -associated conditions, and pharmaceutical compositions containing such compounds.

This application is a Divisional Application of copending, priorapplication Ser. No. 10/997,734, filed on Nov. 24, 2004, which is acontinuation of U.S. application Ser. No. 10/356,158, filed on Jan. 31,2003, which claims priority to U.S. Provisional Application Ser. No.60/353,884, filed on Feb. 1, 2002. The entirety of each of theseapplications is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides for cycloalkyl compounds useful asinhibitors of potassium channel function (especially inhibitors of theK_(v)1 subfamily of voltage gated K⁺ channels, more especiallyinhibitors K_(v)1.5 which has been linked to the ultra-rapidlyactivating delayed rectifier K⁺ current I_(Kur)) and to pharmaceuticalcompositions containing such compounds. The present invention furtherprovides for methods of using such compounds in the treatment ofarrhythmia, I_(Kur)-associated disorders, and other disorders mediatedby ion channel function.

BACKGROUND OF THE INVENTION

The importance of potassium channels was first recognized approximatelyfifty years ago when Hodgkin and Huxley discovered that potassium ionscontributed to the current that excited the squid giant axon. Researchin the area, however, was hampered by the lack of selective, highaffinity ligands for potassium channels. But the advent of recombinantDNA techniques and single cell and whole cell voltage clamp techniqueshas changed the slow pace of the field. Indeed, potassium channels thatexhibit functional, pharmacological and tissue distributioncharacteristics have been cloned. These cloned potassim channels areuseful targets in assays for identifying candidate compounds for thetreatment of various disease states. Potassium channels have turned outto be the most diverse family of ion channels discovered to date. Theymodulate a number of cellular events such as muscle contraction,neuro-endocrine secretion, frequency and duration of action potentials,electrolyte homeostatis, and resting membrane potential.

Potassium channels are expressed in eukaryotic and procaryotic cells andare elements in the control of electrical and non-electrical cellularfunctions. Potassium channels have been classified according to theirbiophysical and pharmacological characteristics. Subclasses of thesechannels have been named based on amino acid sequence and functionalproperties. Salient among these are the voltage dependent potassiumchannels, for example voltage gated potassium channels (e.g., K_(v)1,K_(v)2, K_(v)3, K_(v)4). Subtypes within these subclasses have beencharacterized as to their putative function, pharmacology anddistribution in cells and tissues (Chandy and Gutman, “Voltage-gatedpotassium channel genes” in Handbook of Receptors and Channels—Ligandand Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al.,Curr. Opin. Neurobiol. 5:268, 1995). For example, the K_(v)1 class ofpotassium channels is further subdivided depending on the molecularsequence of the channel, for example K_(v)1.1, K_(v)1.2, K_(v)1.3,K_(v)1.4, K_(v)1.5, K_(v)1.6, and K_(v)1.7. Functional voltage-gated K⁺channels can exist as multimeric structures formed by the association ofeither identical or dissimilar subunits. This phenomena is thought toaccount for the wide diversity of K⁺ channels. However, subunitcompositions of native K⁺ channels and the physiologic role thatparticular channels play are, in most cases, still unclear.

Membrane depolarization by K_(v)1.3 inhibition has been shown to be aneffective method to prevent T-cell proliferation and therefore hasapplications in many autoimmune conditions. Inhibition of K⁺ channels inthe plasma membrane of human T-lymphocytes has been postulated to play arole in eliciting immunosuppressive responses by regulatingintracellular Ca⁺⁺ homeostasis, which has been found to be important inT-cell activation.

The K_(v)1.3 voltage-gated potassium channel is found in neurons, bloodcells, osteoclasts and T-lymphocytes. The Chandy and Cahalanlaboratories proposed a hypothesis that blocking the K_(v)1.3 channelwould elicit an immunosuppressant response. (Chandy et al., J. Exp. Med.160, 369, 1984; Decoursey et al., Nature, 307, 465, 1984). However, theK⁺ channel blockers employed in their studies were non-selective. Untilresearch with the peptide margatoxin, a peptide found in scorpion venom,no specific inhibitor of the K_(v)1.3 channel existed to test thishypothesis. Although a laboratory (Price et al., Proc. Natl, Acad, Sci.USA, 86, 10171, 1989) showed that charybdotoxin would block K_(v)1.3 inhuman T-cells, charybdotoxin was subsequently shown to inhibit fourdifferent K⁺ channels (K_(v)1.3 and three distinct small conductanceCa⁺⁺ activated K⁺ channels) in human T-lymphocytes, limiting the use ofthis toxin as a probe for the physiological role of K_(v)1.3 (Leonard etal., Proc. Natl, Acad. Sci, USA, 89, 10094, 1992). Margatoxin, on theother hand, blocks only K_(v)1.3 in T-cells, and has immunosuppressantactivity on both in in vitro and in vivo models. (Lin et al., J. exp.Med, 177, 637, 1993). The therapeutic utility of this compound, however,is limited by its potent toxicity. Recently, a class of compounds hasbeen reported that may be an attractive alternative to the abovementioned drugs, see for example U.S. Pat. Nos. 5,670,504; 5,631,282;5,696,156; 5,679,705; and 5,696,156. While addressing some of theactivity/toxicity problems of previous drugs, these compounds tend to beof large molecular weight and are generally produced by syntheticmanipulation of a natural product, isolation of which is cumbersome andlabor intensive.

Immunoregulatory abnormalities have been shown to exist in a widevariety of autoimmune and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, Graves ophthalmopathy and asthma.

Although the underlying pathogenesis of each of these conditions may bequite different, they have in common the appearance of a variety ofauto-antibodies and self-reactive lymphocytes. Such self-reactivity maybe due, in part, to a loss of the homeostatic controls under which thenormal immune system operates. Similarly, following a bone-marrow or anorgan transplantation, the host lymphocytes recognize the foreign tissueantigens and begin to produce antibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Anti-inflammatory agents such as NSAID's act principally by blocking theeffect or secretion of these mediators but do nothing to modify theimmunologic basis of the disease. On the other hand, cytotoxic agents,such as cyclophosphamide, act in such a nonspecific fashion that boththe normal and autoimmune responses are shut off. Indeed, patientstreated with such nonspecific immunosuppressive agents are as likely tosuccumb from infection as they are from their autoimmune disease.

Cyclosporin A (CsA), which was approved by the US FDA in 1983 iscurrently the leading drug used to prevent rejection of transplantedorgans. In 1993, FK-506 (Prograf) was approved by the US FDA for theprevention of rejection in liver transplantation. CsA and FK-506 act byinhibiting the body's immune system from mobilizing its vast arsenal ofnatural protecting agents to reject the transplant's foreign protein. In1994, CsA was approved by the US FDA for the treatment of severepsoriasis and has been approved by European regulatory agencies for thetreatment of atopic dermatitis. Though they are effective in fightingtransplant rejection, CsA and FK-506 are known to cause severalundesirable side effects including nephrotoxicity, neurotoxicity, andgastrointestinal discomfort. Therefore, a selective immunosuppressantwithout these side effects still remains to be developed. Potassiumchannel inhibitors promise to be the solution to this problem.

Atrial fibrillation (AF) and atrial flutter are the most common cardiacarrhythmias in clinical practice and are likely to increase inprevalence with the aging of the population. Currently, AF affects morethan 1 million Americans annually, represents over 5% of all admissionsfor cardiovascular diseases and causes more than 80,000 strokes eachyear in the United States. While AF is rarely a lethal arrhythmia, it isresponsible for substantial morbidity and can lead to complications suchas the development of congestive heart failure or thromboembolism.Currently available Class I and Class III antiarrhythmic drugs reducethe rate of recurrence of AF, but are of limited use because of avariety of potentially adverse effects including ventricularproarrhythmia. Because current therapy is inadequate and fraught withside effects, there is a clear need to develop new therapeuticapproaches

Antiarrhythmic agents of Class III are drugs that cause a selectiveprolongation of the duration of the action potential without significantcardiac depression. Available drugs in this class are limited in number.Examples such as sotalol and amiodarone have been shown to possessinteresting Class III properties (Singh B. N., Vaughan Williams E. M. “AThird Class of Anti-Arrhythmic Action: Effects On Atrial And VentricularIntracellular Potentials And Other Pharmacological Actions On CardiacMuscle, of MJ 1999 and AH 3747” Br. J. Pharmacol 1970; 39:675-689. andSingh B. N., Vaughan Williams E. M, “The Effect of Amiodarone, A NewAnti-Anginal Drug, On Cardiac Muscle”, Br J. Pharmacol 1970;39:657-667), but these are not selective Class III agents. Sotalol alsopossesses Class II effects which may cause cardiac depression and iscontraindicated in certain susceptible patients. Amiodarone, also is nota selective Class III antiarrhythmic agent because it possesses multipleelectrophysiological actions and is severely limited by side effects(Nademanee, K. “The Amiodarone Odessey”. J. Am. Coll. Cardiol. 1992;20:1063-1065.) Drugs of this class are expected to be effective inpreventing ventricular fibrillation. Selective class III agents, bydefinition, are not considered to cause myocardial depression or aninduction of arrhythmias due to inhibition of conduction of the actionpotential as seen with Class I antiarrhythmic agents.

Class III agents increase myocardial refractoriness via a prolongationof cardiac action potential duration. Theoretically, prolongation of thecardiac action potential can be achieved by enhancing inward currents(i.e. Na⁺ or Ca²⁺ currents; hereinafter I_(Na) and I_(Ca), respectively)or by reducing outward repolarizing potassium (K⁺) currents. The delayedrectifier (I_(K)) K⁺ current is the main outward current involved in theoverall repolarization process during the action potential plateau,whereas the transient outward (I_(to)) and inward rectifier (I_(KI)) K⁺currents are responsible for the rapid initial and terminal phases ofrepolarization, respectively. Cellular electrophysiologic studies havedemonstrated that I_(K) consists of two pharmacologically andkinetically distinct K⁺ current subtypes, I_(Kr) (rapidly activating anddeactivating) and I_(Ks) (slowly activating and deactivating)(Sanguinetti and Jurkiewicz, Two Components Of Cardiac Delayed RectifierK⁺ Current: Differential Sensitivity To Block By Class IIIAntiarrhythmic Agents, J Gen Physiol 1990, 96:195-215). Class IIIantiarrhythmic agents currently in development, including d-sotalol,dofetilide (UK-68,798), almokalant (H234/09), E-4031 andmethanesulfonamide-N-[1′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl]monochloride,predominantly, if not exclusively, block I_(Kr). Although, amiodarone isa blocker of I_(Ks) (Balser J. R. Bennett, P. B., Hondeghem, L. M. andRoden, D. M. “Suppression Of Time-Dependent Outward Current In GuineaPig Ventricular Myocytes: Actions Of Quinidine And Amiodarone. Circ.Res. 1991, 69:519-529), it also blocks I_(Na) and I_(Ca), effectsthyroid function, is as a nonspecific adrenergic blocker, and acts as aninhibitor of the enzyme phospholipase (Nademanee, K. “The AmiodaroneOdessey”. J. Am. Coll. Cardiol. 1992; 20:1063-1065). Therefore itsmethod of treating arrhythmia is uncertain. Most Class III agents thatare known to be in development predominantly block I_(Kr).

Reentrant excitation (reentry) has been shown to be a prominentmechanism underlying supraventricular arrhythmias in man. Reentrantexcitation requires a critical balance between slow conduction velocityand sufficiently brief refractory periods to allow for the initiationand maintenance of multiple reentry circuits to coexist simultaneouslyand sustain AF. Increasing myocardial refractoriness by prolongingaction potential duration (APD), prevents and/or terminates reentrantarrhythmias. Most selective Class III antiarrhythmic agents currently indevelopment, such as d-sotalol and dofetilide predominantly, if notexclusively, block I_(kr), the rapidly activating component of I_(K)found both in the human atrium and ventricle.

Since these I_(kr) blockers increase APD and refractoriness both inatria and ventricle without affecting conduction per se, theoreticallythey represent potential useful agents for the treatment of arrhythmiaslike AF. These agents have a liability in that they have an enhancedrisk of proarrhythmia at slow heart rates. For example, torsades depoints has been observed when these compounds are utilized (Roden, D. M.“Current Status of Class III Antiarrhythmic Drug Therapy”, Am J.Cardiol, 1993; 72:44B-49B). This exaggerated effect at slow heart rateshas been termed “reverse frequency-dependence”, and is in contrast tofrequency-independent or frequency-dependent actions (Hondeghem, L. M.“Development of Class III Antiarrhythmic Agents”. J. Cadiovasc. Cardiol.20 (Suppl. 2):S17-S22).

The slowly activating component of the delayed rectifier (I_(ks))potentially overcomes some of the limitations of I_(kr) blockersassociated with ventricular arrhythmias. Because of its slow activationkinetics however, the role of I_(ks) in atrial repolarization may belimited due to the relatively short APD of the atrium. Consequently,although I_(ks) blockers may provide distinct advantage in the case ofventricular arrhythmias, their ability to affect SVT is considered to beminimal.

The ultra-rapidly activating delayed rectifier K⁺ current (I_(kur)) isbelieved to represent the native counterpart to a cloned potassiumchannel designated Kv1.5 and, while present in human atrium, it appearsto be absent in human ventricle. Furthermore, because of its rapidity ofactivation and limited slow inactivation, I_(kur) is believed tocontribute significantly to repolarization in human atrium.Consequently, a specific blocker of I_(kur), that is a compound whichblocks Kv1.5, would overcome the short coming of other compounds byprolonging refractoriness by retarding repolarization in the humanatrium without causing the delays in ventricular reporlarization thatunderlie arrhythmogenic after depolarizations and acquired long QTsyndrome observed during treatment with current Class III drugs.

In intact human atrial myocytes an ultra-rapidly activating delayedrectifier K⁺ current I_(kur) which is also known as the sustainedoutward current, I_(sus) or I_(so), has been identified and this currenthas properties and kinetics identical to those expressed by the human K⁺channel clone (hKv1.5, HK2) when isolated from human heart and stablyexpressed in human (HEK-293) cell lines (Wang et al., 1993, Circ Res73:1061-1076; Fedida et al., 1993, Circ Res 73:210-216; Snyders et al.,1993, J Gen Physiol 101:513-543) and originally cloned from rat brain(Swanson et al., 10, Neuron 4:929-939). Although various antiarrythmicagents are now available on the market, those having both satisfactoryefficacy and a high margin of safety have not been obtained. Forexample, antiarrythmic agents of Class I according to the classificationscheme of Vaughan-Williams (“Classification Of Antiarrhythmic Drugs: In:Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K.Olesen; Sweden, Astra, Sodertalje, pp449-472, 1981) which cause aselective inhibition of the maximum velocity of the upstroke of theaction potential (_(max)) are inadequate for preventing ventricularfibrillation. In addition, they have problems regarding safety, namely,they cause a depression of myocardial contractility and have a tendencyto induce arrhythmias due to an inhibition of impulse conduction.Beta-adrenoceptor blockers and calcium antagonists which belong to ClassII and IV, respectively, have a defect in that their effects are eitherlimited to a certain type of arrhythmia or are contraindicated becauseof their cardiac depressant properties in certain patients withcardiovascular disease. Their safety, however, is higher than that ofthe antiarrhythmic agents of Class I.

SUMMARY OF THE INVENTION

The present invention provides cycloalkyl compounds of the followingformula I, including enantiomers, diastereomers, and salts thereof,useful as inhibitors of potassium channel function (especiallyinhibitors of the K_(v)1 subfamily of voltage gated K⁺ channels, moreespecially inhibitors of K_(v)1.5 which has been linked to theultra-rapidly activating delayed rectifier K⁺ current, I_(Kur)) for thetreatment of disorders such as arrhythmia and I_(Kur)-associateddisorders:

including enantiomers, diastereomers and salts thereof wherein thedashed line represents an optional double bond, provided that R^(1a) isabsent when a

double bond is present;

-   m and p are independently 0, 1, 2 or 3;-   R¹ is-    —SO₂R^(8c), —CO₂H, —OC(O)CCl₃, —C(O)R^(8c), —CO₂R^(8c),    —C(═S)R^(8c), —NR⁶R⁷, —OC(O)NR⁶R⁷, —N₃, optionally substituted aryl,    optionally substituted heteroaryl, optionally substituted    heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy, optionally    substituted alkoxy, optionally substituted aryloxy, optionally    substituted heteroaryloxy, optionally substituted alkyl, optionally    subsituted alkenyl, or optionally subsituted alkynyl;-   R^(1a) is H or R^(X);-   or R¹ and R^(1a) together form oxo;-   or R¹ and R^(1a) together with the carbon atom to which they are    attached combine to form an optionally substituted spiro-fused    heterocyclo group;-    or R¹ and R^(1a) together combine to form a group;-   R² is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,    (heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may    be optionally independently substituted with one or more groups T¹,    T² or T³;-   J is a bond, C₁₋₄ alkylene optionally independently substituted with    one or more groups T^(1a), T^(2a) or T^(3a), or C₁₋₄ alkenylene    optionally independently substituted with one or more groups T^(1a),    T^(2a) or T^(3a);-   R³ is-    R⁴ is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or    heteroaryl any of which may be optionally independently substituted    with one or more groups T^(1b), T^(2b) or T^(3b);-   R^(4a) is R⁴ or OR⁴;-   R⁵ is —NR^(6a)R^(7a), or heteroaryl, (heteroaryl)alkyl, aryl,    (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo,    (heterocyclo)alkyl, alkyl, alkenyl or alkynyl any of which may be    optionally independently substituted with one or more groups T^(1c),    T^(2c) or T^(3c);-   R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8a1), R^(8a2), R^(8a3),    R^(8a4), R^(8a5) and R⁹ are independently H, alkyl, hydroxy, alkoxy,    aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,    (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,    (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,    cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,    (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R¹²,    —CO₂R¹², —C(O)—NR¹²R¹³, or —NR¹²R¹³ any of which may be optionally    independently substituted with one or more groups T^(1d), T^(2d) or    T^(3d);-   or R⁶ and R⁷, or R^(6a) and R^(7a) together with the nitrogen atom    to which they are attached may combine to form a saturated or    unsaturated 4 to 8 membered ring (either cycloalkyl or heterocylco)    optionally independently substituted with one or more groups T^(1d),    T^(2d) or T^(3d);-   or one of R⁶ or R⁷, may combine with one of R⁸, R^(8a) or R⁹ to form    a saturated or unsaturated 5 to 8 membered ring (either cycloalkyl    or heterocylco) optionally independently substituted with one or    more groups T^(1d), T^(2d) or T^(3d).-   or one of R^(6a) or R^(7a), may combine with R^(8a1) to form a    saturated or unsaturated 5 to 8 membered ring (either cycloalkyl or    heterocylco) optionally independently substituted with one or more    groups T^(1d), T^(2d) or T^(3d)-   R^(8b) is independently H, alkyl, aryl, cyano, nitro, acyl or    —SO₂(alkyl);-   R^(8c) is independently H, alkyl, cycloalkyl, alkenyl, alkynyl,    aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;-   R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴, CONR⁶R⁷, or SO₂—NR⁶R⁷;-   R¹⁰ R^(10a), R¹¹ and R^(11a) are independently H, alkyl, aryl,    (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl,    amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo,    (heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or    cyano any of which may be optionally independently substituted on    available atoms (as allowed by valence) with one or more groups    T^(1e), T^(2e) or T^(3e);-   or R¹⁰ and R^(10a), or R¹¹ and R^(11a) may combine to form oxo;-   or R^(10a) may combine with R^(11a) to form a bond;-   or R¹⁰ may combine with R⁹ to form a saturated or unsaturated ring;-   R¹² and R¹³ are independently H, alkyl, hydroxy, alkoxy, aryloxy,    heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl,    (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl,    cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,    (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which    may be optionally independently substituted with one or more groups    T^(1f), T^(2f) or T^(3f)-   or R¹² and R¹³ together with the nitrogen atom to which they are    attached may combine to form a saturated or unsaturated ring (either    cycloalkyl or heterocylco) which may be optionally independently    substituted with one or more groups T^(1f), T^(2f) or T^(3f);-   W is ═NR^(8a2), ═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or    ═N—SO₂R^(8a2);-   X is-   Z, Z¹ and Z² are independently ═O, ═S, ═NR^(8a4) or ═N—CN;-   R¹⁴ is independently    -   where q is 1, 2 or 3;    -   R^(Y) is an optional oxo substituent attached to any available        ring carbon atom;    -   X¹ is O, S, NR^(8a5) or CH₂; and    -   X² is NR^(8a5) or CH₂;-   R^(X) is one or more optional substituents, attached to any    available ring carbon atom, independently selected from T^(1g),    T^(2g) or T^(3g);-   T^(1-1g), T^(2-2g), and T^(3-3g) are are each independently    -   (1) hydrogen or T⁶, where T⁶ is        -   (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,            cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,            (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,            (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;        -   (ii) (ii) a group (i) which is itself substituted by one or            more of the same or different groups (i); or        -   (iii) (iii) a group (i) or (ii) which is independently            substituted by one or more (preferably 1 to 3) of the            following groups (2) to (13) of the definition of T^(1-1g),            T^(2-2g) and T^(3-3g),    -   (2) —OH or —OT⁶,    -   (3) —SH or —ST⁶,    -   (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶, where t is 1 or 2;    -   (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶,    -   (6) halo,    -   (7) cyano,    -   (8) nitro,    -   (9) -T⁴-NT⁷T⁸    -   (10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸,    -   (11) -T⁴-N(T¹⁰)-T⁵-T⁶,    -   (12) -T⁴-N(T¹⁰)-T⁵-H,    -   (13) oxo,-   T⁴ and T⁵ are each independently    -   (1) a single bond,    -   (2) -T¹¹-S(O)_(t)-T¹²,    -   (3) -T¹¹-C(O)-T¹²,    -   (4) -T¹¹-C(S)-T¹²,    -   (5) -T¹¹-O-T¹²-,    -   (6) -T¹¹-S-T¹²-,    -   (7) -T¹¹-O—C(O)-T¹²-,    -   (8) -T¹¹-C(O)—O-T¹²-,    -   (9) -T¹¹-C(═NT^(9a))-T¹²-, or    -   (10) -T¹¹-C(O)—C(O)-T¹²--   T⁷, T⁸, T⁹, T^(9a) and T¹⁰    -   (1) are each independently hydrogen or a group provided in the        definition of T⁶, or    -   (2) T⁷ and T⁸ may together be alkylene or alkenylene, completing        a 3- to 8-membered saturated or unsaturated ring together with        the atoms to which they are attached, which ring is        unsubstituted or substituted with one or more groups listed in        the description of T^(1-1g), T^(2-2g) and T^(3-3g), or    -   (3) T⁷ or T⁸, together with T⁹, may be alkylene or alkenylene        completing a 3- to 8-membered saturated or unsaturated ring        together with the nitrogen atoms to which they are attached,        which ring is unsubstituted or substituted with one or more        groups listed in the description of T^(1-1g), T^(2-2g) and        T^(3-3g), or    -   (4) T⁷ and T⁸ or T⁹ and T¹⁰ together with the nitrogen atom to        which they are attached may combine to form a group —N═CT¹³T¹⁴        where T¹³ and T¹⁴ are each independently H or a group provided        in the definition of T⁶; and-   T¹¹ and T¹² are each independently    -   (1) a single bond,    -   (2) alkylene,    -   (3) alkenylene, or    -   (4) alkynylene.

The present invention provides novel methods for the prevention andtreatment of arrhythmia and I_(Kur)-associated disorders employing oneor more compounds of the formula I, enantiomers, diastereomers orpharmaceutically acceptable salts thereof In particular the presentinvention provides a novel method for the selective prevention andtreatment of supraventricular arrhythmias.

Preferred compounds within the scope of formula I include compounds offormula I_(a), I_(b) and I_(c):

Preferred compounds within the scope of formula I include compounds andsalts thereof wherein one or more, and especially all of R¹, R^(1a), R²,J and R³ are selected from the following definitions:

-   R¹ is hydrogen, hydroxy, —NR⁶R⁷, —O—C(O)—NR⁶R⁷, —O—C(O)—R⁴,    —N(R⁸)—SO₂—NR⁶R⁷, —N(R⁸)—C(Z)-N(R^(8a))—SO₂—R⁴,    —N(R⁸)—C(Z)-N(R^(8a))—SO₂—OH, —SO₂—R^(8c), —N(R⁸)—C(W)—NR⁶R⁷, or a    group-   R^(1a) is H, or R^(1a) and R¹ combine from oxo or an optionally    substituted spiro-fused heterocyclo group;-   R² is optionally substituted alkyl, optionally substituted alkenyl,    optionally substituted aryl (especially phenyl or napthyl),    optionally substituted (aryl)alkyl (especially benzyl), or    optionally substituted heteroaryl (especially thienyl, benzothienyl,    pyridinyl or isoxazolyl);-   J is a bond, optionally substituted C₁₋₄ alkylene (especially    methylene) or optionally substituted C₁₋₄ alkenylene (especially    ethenylene);-   R³ is —R⁵, —OR⁵, —C(Z¹)-R⁵, —C(Z¹)-O—R⁵, —O—C(Z¹)-R⁵,    —N(R^(8a1))—C(Z¹)-R⁵, —N(R^(8a1))—C(Z¹)-O—R⁵ or —N(R^(8a1))—SO₂—R⁵;-   R⁵is optionally substituted aryl, optionally substituted    (aryl)alkyl, optionally substituted heteroaryl, optionally    substituted (heteroaryl)alkyl, optionally substituted heterocylco,    optionally substituted (heterocylco)alkyl, optionally subsituted    cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally    substituted alkyl, optionally substituted alkenyl, optionally    substituted alkynyl, —NR^(6a)R^(7a) or a group,-   R⁶, R^(6a), R⁷ and R^(7a) are independently H, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted cycloalkyl, optionally substituted heterocyclo,    optionally substituted (aryl)alkyl, optionally substituted    (heteroaryl)alkyl, optionally substituted (heterocylco)alkyl,    optionally substituted alkyl, or COR¹²;-   or R⁶ and R⁷, or R^(6a) and R^(7a) together with the nitrogen to    which thery are attached combine to form an optionally substituted    saturated or unsaturated 5 to 8 membered ring; and-   R⁴, R⁸, R^(8a1), R^(8c), R⁹, R¹⁰, R^(10a), R¹¹, R^(11a), R^(X), X,    X¹, Z¹ and W are as defined above.

More preferred compounds within the scope of formula I include compoundsand salts thereof wherein one or more, and especially all of R¹, R^(1a),R², J and R³ are selected from the following definitions:

-   R¹ is hydrogen, hydroxy, —O—C(O)—NR⁶R⁷, —O—C(O)—R⁴,    —N(R⁸)—SO₂—NR⁶R⁷, —SO₂—R^(8c), —N(R⁸)—C(W)—NR⁶R⁷,    —N(R⁸)—C(Z)-N(R^(8a))—SO₂—R⁴, —N(R⁸)—C(Z)-N(R^(8a))—SO₂—OH, or a    group-   R^(1a) is H,;-   R² is phenyl, napthyl, thienyl benzothienyl, alkyl or alkenyl any of    which may be optionally substituted as described above;-   J is a bond, methylene or ethylene;-   R³ is —R⁵, —C(Z¹)-R⁵, —O—C(Z¹)-R⁵, or —N(R^(8a1))—C(Z¹)-R⁵;-   R⁵ is optionally substituted alkyl, optionally substituted    cycloalkyl, optionally substituted heteroayl, optionally substituted    aryl or —NR^(6a)R^(7a);-   R⁶, R^(6a), R⁷ and R^(7a) are independently H, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted cycloalkyl, optionally substituted heterocyclo,    optionally substituted (aryl)alkyl, optionally substituted    (heteroaryl)alkyl, optionally substituted (heterocylco)alkyl,    optionally substituted alkyl, or COR¹²;-   or R⁶ and R⁷, or R^(6a) and R^(7a) together with the nitrogen to    which thery are attached combine to form an optionally substituted    saturated or unsaturated 5 to 8 membered ring; and-   R⁴, R⁸, R^(8a1), R^(8c), R⁹, R¹⁰, R^(10a), R¹¹, R^(11a), X, Z¹ and    Ware as defined above.

Most preferred compounds within the scope of formula I include compoundsand salts thereof wherein one or more, and especially all of R¹, R^(1a),R², J and R³ are selected from the following definitions:

-   R¹ is    -   (a) hydrogen, or hydroxy;    -   (b) —O—C(O)—NR⁶R⁷, —N(R⁸)—SO₂—NR⁶R⁷, or —N(R⁸)—C(W)—NR⁶ R⁷ where        -   R⁶ and R⁷ are independently            -   (i) H, or            -   (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl,                heteroaryl, heterocyclo, alkoxy, (aryl)alkyl,                (cycloalkyl)alkyl, (heteroaryl)alkyl,                (heterocyclo)alkyl, (alkoxy)alkyl, or NR12R¹³ any of                which may be optionally independently substituted with                one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano,                halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,                heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl,                (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,                (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or                (heterocyclo)alkyl,            -   or R⁶ and R⁷ combine to form a heterocylo ring                optionally substituted with one or more OH, SH, OT⁶,                ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl,                haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,                (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl,                (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,                (heteroaryl)alkyl or (heterocyclo)alkyl; and            -   R⁸ is                -   (i) H; or                -   (ii) alkyl, cycloalkyl, aryl, heteroaryl,                    heterocyclo, (cycloalkyl)alky, (aryl)alkyl,                    (heteroaryl)alkyl or (heterocyclo)alkyl any of which                    may be optionally independently substituted with one                    or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano,                    halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,                    heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl,                    (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,                    (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or                    (heterocyclo)alkyl,    -   (c) —O—C(O)—R⁴, —N(R⁸)—C(Z)-N(R^(8a))—SO₂—R⁴ or        —N(R⁸)—C(Z)-N(R^(8a))—SO₂—OH where        -   R⁴ is            -   (i) H, or            -   (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl,                heteroaryl, heterocyclo, alkoxy, (aryl)alkyl,                (cycloalkyl)alkyl, (heteroaryl)alkyl,                (heterocyclo)alkyl, (alkoxy)alkyl, or NR¹²R¹³ any of                which may be optionally independently substituted with                one or more OH, SH, OT⁶, ST⁶, C(O)_(T) ⁶, NT⁷T⁸, cyano,                halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,                heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl,                (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,                (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or                (heterocyclo)alkyl; and        -   R⁸ and R^(8a) are independently            -   (i) H; or            -   (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,                (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or                (heterocyclo)alkyl any of which may be optionally                independently substituted with one or more OH, SH, OT⁶,                ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl,                haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,                (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl,                (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,                (heteroaryl)alkyl or (heterocyclo)alkyl; or    -   (d) or a group-   R^(1a) is H,;-   R² is phenyl, (phenyl)alkyl, napthyl, thienyl benzothienyl, alkyl or    alkenyl any of which may be optionally independently substituted    with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo,    oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,    (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,    (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl;-   J is a bond, methylene or ethylene;-   R³ is    -   (a) —R⁵ or where R⁵ is heteroaryl, heterocyclo or —NR^(6a)R^(7a)        any of which may be optionally independently substituted with        one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo,        oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,        (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl,        (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or        (heterocyclo)alkyl;    -   (b) —C(Z¹)-R⁵, or —O—C(Z¹)-R⁵, where        -   R⁵ is aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl) or            —NR^(6a)R^(7a); and        -   R^(6a) and R^(7a) are independently            -   (i) H; or            -   (ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl, heteroaryl                (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any                of which may be optionally independently substituted                with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸,                cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,                heterocyclo, 10 (OH)alkyl, (SH)alkyl, (OT⁶)alkyl,                (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,                (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or                (heterocyclo)alkyl; or    -   (c) —N(R^(8a1))—C(Z¹)-R⁵, or —N(R^(8a1))—SO₂—R⁵ where        -   R⁵ is aryl, (aryl)alkyl, hetreoaryl, (heteroaryl)alkyl,            heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl, alkynyl,            cycloalkyl, (alkoxy)alkyl, or (cycloalkoxy)alkyl any of            which may be optionally independently substituted with one            or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo,            oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,            (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,            (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,            (heteroaryl)alkyl or (heterocyclo)alkyl; and        -   R^(8a1) is            -   (i) H; or            -   (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,                (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or                (heterocyclo)alkyl any of which may be optionally                independently substituted with one or more OH, SH, OT⁶,                ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl,                haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,                (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl,                (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,                (heteroaryl)alkyl or (heterocyclo)alkyl,-   R⁵ is optionally substituted alkyl, optionally substituted    cycloalkyl, optionally substituted heteroayl, optionally substituted    aryl or —NR^(6a)R^(7a);-   R⁶, R^(6a), R⁷ and R^(7a) are independently H, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted cycloalkyl, optionally substituted heterocyclo,    optionally substituted (aryl)alkyl, optionally substituted    (heteroaryl)alkyl, optionally substituted (heterocylco)alkyl,    optionally substituted alkyl, or COR¹²;-   or R⁶ and R⁷, or R^(6a) and R^(7a) together with the nitrogen to    which thery are attached combine to form an optionally substituted    saturated or unsaturated 5 to 8 membered ring; and-   R⁴, R⁸, R^(8a1), R^(8c), R⁹, R¹⁰, R^(10a), R¹¹, R^(11a), X, Z¹ and W    are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower alkyl groups, that is,alkyl groups of 1 to 6 carbon atoms, are generally most preferred. Theterm “substituted alkyl” refers to alkyl groups substituted with one ormore groups listed in the definition of T^(1-1g), T^(2-2g) and T^(3-3g),preferably selected from cyano, halo, oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶,—OC(O)T⁶, -T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶, —S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, andat least one double carbon to carbon bond (either cis or trans), such asethenyl. The term “substituted alkenyl” refers to alkenyl groupssubstituted with one or more groups listed in the definition ofT^(1-1g), T^(2-2g) and T^(3-3g), preferably selected from cyano, halo,oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶, —OC(O)T⁶, -T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶,—S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, andat least one triple carbon to carbon bond, such as ethynyl. The term“substituted alkynyl” refers to alkynyl groups substituted with one ormore groups listed in the definition of T^(1-1g), T^(2-2g) and T^(3-3g),preferably selected from cyano, halo, oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶,—OC(O)T⁶-T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶, —S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶.

The term “alkylene” refers to a straight chain bridge of I to 4 carbonatoms connected by single bonds (e.g., —(CH₂)_(x)— wherein x is 1 to 5),which may be substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), preferably selected fromcyano, halo, oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶, —OC(O)T⁶, -T⁴-NT⁷T⁸,-T⁴-N(T⁹)-T⁵-T⁶, —S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶.

The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbonatoms having one or two double bonds that is connected by single bondsand may be substituted with one or more groups listed in the definitionof T^(1-1g), T^(2-2g) and T^(3-3g), preferably selected from cyano,halo, oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶, —OC(O)T⁶, -T⁴-NT⁷T⁸,-T⁴-N(T⁹)-T⁵-T⁶, —S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶. Exemplary alkenylenegroups are —CH═CH—CH═CH—, —CH₂—CH═CH—, —CH₂—CH═CH—CH₂—, —C(CH₃)₂CH═CH—and —CH(C₂H₅)—CH═CH—.

The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbonatoms that has a triple bond therein, is connected by single bonds, andmay be substituted with one or more groups listed in the definition ofT^(1-1g), T^(2-2g) and T^(3-3g), preferably selected from cyano, halo,oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶, —OC(O)T⁶, -T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶,—S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶. Exemplary alkynylene groups are —C≡C—,—CH₂—C≡C—, —CH(CH₃)—C≡C— and —C≡C—CH(C₂H₅)CH₂—.

The terms “ar” or “aryl” refer to aromatic homocyclic (i.e.,hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferablyhaving 6 to 14 members such as phenyl, naphthyl and biphenyl, as well assuch rings fused to a cycloalkyl, cycloalkenyl, heterocyclo, orheteroaryl ring. Examples include:

and the like.

The term “substituted aryl” refers to aryl groups substituted with oneor more groups listed in the definition of T^(1-1g), T^(2-2g) andT^(3-3g), preferably selected cyano, halo, oxo, hydroxy, —OT⁶,—C(O)_(t)T⁶, —OC(O)T⁶, -T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶, —S(O)_(t)T⁶ or—S(O)_(t)N(T⁹)T⁶.

The term “cycloalkyl” refers to saturated and partially unsaturated(containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl,containing a total of 3 to 20 carbons forming the rings, preferably 3 to7 carbons, forming the ring and which may be fused to 1 or 2 aromatic orheterocyclo rings, which include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl,cyclohexenyl,

and the like. The terms “substituted cycloalkyl” refers to cycloalkylgroups substituted with one or more groups listed in the definition ofT^(1-1g), T^(2-2g) and T^(3-3g), preferably selected from cyano, halo,oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶, —OC(O)T⁶, -T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶,—S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclo” refer to fully saturated or partially or unsaturatedcyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 memberbicyclic, or 10 to 20 member tricyclic ring systems, preferablycontaining a total of 3 to 10 ring atoms) which have at least oneheteroatom in at least one carbon atom-containing ring. Each ring of theheterocyclic group containing a heteroatom may have 1, 2, 3 or 4heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfuratoms, where the nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be substituted orquatemized. The heterocyclic group may be attached at any heteroatom orcarbon atom of the ring or ring system. The rings of multi-ringheterocycles may be either fused, bridged and/or joined through one ormore spiro unions. Exemplary heterocyclic groups include

and the like.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclo” refer toheterocycle, heterocyclic and heterocyclo groups substituted with one ormore groups listed in the definition of T^(1-1g), T^(2-2g) and T^(3-3g),preferably selected from cyano, halo, oxo, hydroxy, —OT⁶, —C(O)_(t)T⁶,—OC(O)T⁶, -T⁴-NT⁷T⁸, -T⁴-N(T⁹)-T⁵-T⁶, —S(O)_(t)T⁶ or —S(O)_(t)N(T⁹)T⁶.

The term “heteroaryl” as used herein alone or as part of another grouprefers to a 5- 6- or 7-membered aromatic rings containing from 1 to 4nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that thering contains at least 1 carbon atom and no more than 4 heteroatoms. Theheteroaryl ring is linked through an available carbon or nitrogen atom.Also included within the definition of heteroaryl are such rings fusedto a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring.One, two, or three available carbon or nitrogen atoms in the heteroarylring can be optionally substituted with substituents listed in thedescription of T₁, T₂ and T₃. Also an available nitrogen or sulfur atomin the heteroaryl ring can be oxidized. Examples of heteroaryl ringsinclude

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of the formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety andan acidic moiety, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful, e.g., in isolation orpurification steps which may be employed during preparation. Salts ofthe compounds of the formula I may be formed, for example, by reacting acompound I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

The compounds of formula I which contain a basic moiety may form saltswith a variety of organic and inorganic acids. Exemplary acid additionsalts include acetates (such as those formed with acetic acid ortrihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety may form saltswith a variety of organic and inorganic bases. Exemplary basic saltsinclude ammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as benzathines, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quatemized with agents such aslower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g. benzyl and phenethyl bromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I are preferably hydrates.

To the extent that compounds of the formula I, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the various R and Z substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons) and diastereomeric forms, are contemplated withinthe scope of this invention. Individual stereoisomers of the compoundsof the invention may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the presentinvention can have the S or R configuration as defined by the IUPAC 1974Recommendations.

The terms “including”, “such as”, “for example” and the like areintended to refer to exemplary embodiments and not to limit the scope ofthe present invention.

Schemes

Compounds of the formula I may be prepared using the sequence of stepsoutlined below. Specifically, compounds of the formula I where R1 is—O—CO—NR⁶R⁷, R² is aryl, substituted aryl or heteroaryl and -J-R³ is—CH₂—NH—CO—R⁵ may be prepared using Scheme 1.

Bis Michael addition to acetonitrile 2 and subsequent Dieckmanncondensation yields the intermediate cyclohexyl β-keto ester 4. Krapchodecarboxylation to the ketone followed by ketone protection andreduction of the nitrile 6 generates the primary amine 7. The amine issubsequently acylated, deprotected and the resulting ketone 9 reduced.The cis and trans alcohols may be separated and taken on to finalproduct esters and carbamates.

Compounds of the formula I where R¹ is —NR⁸—C(NCN)—NR⁶R⁷, R² is aryl,substituted aryl or heteroaryl and -J-R³ is —CH₂—NH—CO—R⁵ may beprepared using Scheme 2.

Protection of the ketone moiety of commercially available compound 1,followed by reduction of nitrile with LAH provides the amine 3. Theamine is acylated and the ketal moiety deprotected to provide the ketone4. Reductive amination produces the amine 5. Compounds of formula 6 maybe prepared by displacement of phenoxy group from diphenyl cyanourea.Warming 6 and an amine at 60 -75° C. in alcoholic solvents provides thecompound 7.

Alternatively, compounds of the formula I where R¹ is —NR⁸—C(NCN)—NR⁶R⁷,R² is aryl, substituted aryl or heteroaryl and -J-R³ is —CH₂—NH—CO—R⁵may be prepared using Scheme 3.

Compound 1 used in this preparation is readily prepared fromcommercially available reagents by the methods well known to thoseskilled in the art. Assembly of substituted cyclohexyl cyanoguanidinessuch as compound 3 can be done using methodology described in Scheme 2.Hydrolysis of the TFA protecting group and acylation of the amine 4 mayprovide the compounds of formula 5.

Compounds of the formula I where R¹ is —NH—SO₂—NR⁶R⁷, R² is aryl,substituted aryl or heteroaryl and -J-R³ is —CH₂—NH—CO—R⁵ may beprepared using Scheme 4.

The amine 1 may be converted to the corresponding sulfonyl oxazolidinein a way described in the literature (Dewynter, G., et als. Tetrahedron,1996, 52, 14217-14224). Compounds of formula 3 may be prepared bydisplacement reaction of oxazolidine 2 with amines at temperature of65-75° C. in alcholic solvents such as ethanol and isopropanol.

Compounds of the formula I where R¹ is —NH—C(═NCO₂R⁸)—NR⁶R⁷, R² is aryl,substituted aryl or heteroaryl and -J-R³ is —CH₂—NH—CO—R⁵ may beprepared using Scheme 5.

Treatment of the amine 1 with isothiocyanoformate may provide thethiourea 2, which would provide the compounds of formula 3 by thecoupling with the amine in the presence of EDCI.

Compounds of the formula I where R¹ is a hydantoin heterocycle, R² isaryl, substituted aryl or heteroaryl and -J-R³ is —CH₂—NH—CO—R⁵ may beprepared using Scheme 6.

The isocyanate 2 could be obtained upon treating the amine 1 withphosgene. Treatment of the isocyanate 2 with substituted aminoester at65-75° C. in alcoholic solvents such as ethanol or isopropanol canprovide the compounds of formula 3.

Alternatively, compounds of formula 3 could be obtained by treating theamine I with substituted isocyanoactate in proper solvents such asdichloromethane or THF, followed by ring closure under acidic conditionsaccording to Scheme 7.

Compounds of the formula I where R¹ is an imidazolidine-2-oneheterocycle, R² is aryl, substituted aryl or heteroaryl and -J-R³ is—CH₂—NH—CO—R⁵ may be prepared using Scheme 8.

Reductive amination of the ketone 1 with the substituted ethylenediamine2 may provide cyclohexylamine 3. The amine 3 can be converted to thecorresponding cyclic ureas of formula 5 upon treatment with carbonyldiimidazole 4 in a solvent such as THF or dichloromethane.

Compounds of the formula I where R¹ is an imidazolidine-2-ylidinecyanamide heterocycle, R² is aryl, substituted aryl or heteroaryl and-J-R³ is —CH₂—NH—CO—R⁵ may be prepared using Scheme 9.

The same intermediate 1 from Scheme 7 may produce the compounds offormula 3 upon treating it with diphenyl cyanocarbonidate 2 attemperature of 65-75° C. in alcholic solvents such as ethanol orisopropanol.

Compounds of the formula I where -J-R³ is —CH₂—NH—R⁶ where R⁶ is aryl orheteroaryl may be prepared using Scheme 10.

The intermediate 1 may react with a substituted aryl or heteroarylcompound where X is Cl, Br, I, OTf or similar leaving group in thepresence of a palladium catalyst such as Pd₂(dba)₃ to produce compound2.

Compounds of the formula I where -J-R³ is —CONR⁶R⁷ may be prepared usingScheme 11

The carboxylic acid 1 may be made to react with amine HNR⁶R⁷ using avariety of standard coupling procedures known in the literature to giveamide compounds of formula 2. Activation of the carboxylic acid byconversion to the carboxylic acid chloride or carboxylic acid fluoridein a solvent such as methylene chloride or acetonitrile followed byreaction with an amine in the presence of a base such as triethylamineor pyridine is a particularly useful coupling procedure.

Compounds of the formula I where R¹ is —O—CO—NR⁶R⁷, and -J-R³ is aheterocycle, for example oxadiazole, can be prepared using Scheme 12.

Nitrile 1 may be made to react with hydoxylamine in an organic solventsuch as n-propanol to give carboxamidine 2. Carboxamidine 2 may beacylated with a variety of carboxylic acids, carboxylic acid chloridesor carboxylic acid fluorides using standard coupling procedures and theresulting intermediates may be made to undergo cyclization upon heatingto give 1,2,4-oxadiazole 3. Deprotection of the ketal group of the1,2,4-oxadiazole 3 followed by reduction of the ketone using a reducingagent such sodium borohydride in an organic solvent such astetrahydrofuran gives hydroxy compound 4. The hydroxy compound 4 may beconverted to the carbamate 5 by first reacting the hydroxy derivativewith 4-nitrophenyl chloroformate to obtain the carbonate intermediatewhich is then reacted with an amine to form the carbamate.

Compounds of the formula I where R1 is —O—CO—NR⁶R⁷, and -J-R3 is aheterocycle, for example tetrazole, can be prepared using Scheme 13.

Nitrile 1 may be made to react with sodium azide in a organic solventsuch as N,N-dimethylformamide at elevated temperatures to form thetetrazole 2. The tetrazole 2 may be alkylated by treatment with an alkylhalide in the presence of a base such as potassium carbonate in anorganic solvent such as aceteonitrile. Deprotection of the ketal groupof the alkylated tetrazole 3 followed by reduction of the ketone using areducing agent such sodium borohydride in an organic solvent such astetrahydrofuran gives the hydroxy compound 4. The hydroxy compound 4 maybe converted to the carbamate 5 by first reacting the hydroxy derivativewith 4-nitrophenyl chloroformate to obtain the carbonate intermediatewhich is then reacted with an amine to form the carbamate.

Compounds of the formula I where -J-R³ is a heterocycle, for example3H-quinazolin-4-one, can be prepared using Scheme 14.

The carboxylic acid 1 may react with an anthranilic acid using a varietyof standard coupling procedures known in the literature to give amidecompound 2. Cyclization of compound 2 under basic conditions in anorganic solvent such as ethanol at elevated temperatures would givecompounds of formula 3.

Compounds of the formula I where -J-R³ is a heterocycle, for examplebenzoxazole, can be prepared using Scheme 15.

The carboxylic acid 1 may be made to react with a 2-aminophenolderivative using a variety of standard coupling procedures known in theliterature to give amide compound 2. Cyclization of compound 2 underacidic conditions in an organic solvent such as p-xylene at elevatedtemperatures would give compounds of formula 3

Compounds of the formula I where -J-R³ is a heterocycle, for examplebenzimidazole, can be prepared using Scheme 16.

The carboxylic acid 1 may be made to react with an o-phenylenediaminederivative using a variety of standard coupling procedures known in theliterature to give amide compound 2. Cyclization of compound 2 underacidic conditions in a solvent such as acetic acid at elevatedtemperatures would give compounds of formula 3.

Compounds of the formula I where -J-R³ is —CO—NR^(6a)R^(7a) and R¹ is—O—CO—NR⁶R⁷ can be prepared using Scheme 17.

The nitrile 1 may be converted to the carboxylic acid 2 by treatmentwith a base such as sodium hydroxide in a solvent such as ethyleneglycol at elevated temperatures. The carboxylic acid 2 may be made toreact with an amine HNR^(6a)R^(7a) using a variety of standard couplingprocedures known in the literature to give amide compounds 3.Deprotection of the ketal group of the amide 3 followed by reduction ofthe ketone using a reducing agent such as sodium borohydride in anorganic solvent such as tetrahydrofuran gives the hydroxy compound 4.The hydroxy compound 4 may be converted to the carbamate of formula 5 byfirst reacting the hydroxy derivative 4 with 4-nitrophenyl chloroformateto obtain the carbonate intermediate which is then reacted with HNR⁶R⁷to form the carbamate.

Compounds of the formula I where -J-R³ is —CO—NR^(6a)R^(7a) and R¹ is—NR⁸—CO—R⁴ can be prepared using Scheme 18.

The carboxylic acid 1 may be made to react with an amine HNR^(6a)R^(7a)using a variety of standard coupling procedures known in the literatureto give amide compounds 2. Deprotection of the ketal group of the amide2 followed by reductive amination of the ketone by first treating theketone with amine H₂NR⁸ to form the imine intermediate followed byreduction of the imine with a reducing agent such as and sodiumcyanoborohydride in an organic solvent such as methanol gives the aminocompound 3. The amino compound 3 may be made to react with a carboxylicacid R⁴CO₂H using a variety of standard coupling procedures to givecompound 4.

Compounds of the formula I where -J-R³ is —CONR^(6a)R^(7a) and R¹ is—NR⁸—C(NCN)—NR⁶R⁷ can be prepared using Scheme 19.

Amine 1 may react with diphenylcyanocarbonimidate in a solvent such asacetonitrile at elevated temperature to give an intermediate 2 which canfurther react with amine HNR⁶R⁷ to give compound 3.

Compounds of formula I wherein -J-R³ is an (amino)methyl group may beprepared using methodology such as that described in Example 323 or thefollowing schemes 20 and 21.

Additional compounds within the scope of the present invention can beprepared from the compounds obtained by the above described methodsthrough conversion of the substituent groups to other functionality bythe usual methods of chemical synthesis, as illustrated in the followingexamples.

Compounds of formula I that contain chiral centers may be obtained innon-racemic form by non-racemic synthesis or resolution by methods wellknown to those skilled in the art. Compounds that are non-racemic aredesignated as “chiral” in the examples.

In the examples described below it may be necessary to protect reactivefunctionality such as hydroxy, amino, thio or carboxy groups, wherethese are desired in the final product, to avoid their unwantedparticipation in reactions. The introduction and removal of protectinggroups are well known to those skilled in the art, for example see(Green, T. W. in “Protective Groups in Organic Synthesis”, John Wileyand Sons, 1991).

Utility

Compounds within the scope of the present invention inhibit the K_(v)1subfamily of voltage-gated K⁺ channels, and as such are useful in thetreatment and/or prevention of various disorders: cardiac arrhythmias,including supraventricular arrhythmias, atrial arrhythmias, atrialflutter, atrial fibrillation, complications of cardiac ischemia, and useas heart rate control agents; angina pectoris including relief ofPrinzmetal's symptoms, vasospastic symptoms and variant symptoms;gastrointestinal disorders including reflux esauphagitis, functionaldispepsia, motility disorders (including constipation and diarrhea), andirritable bowel syndrome; disorders of vascular and visceral smoothmuscle including asthma, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, peripheral vascular disease (includingintermittent claudication), venous insufficiency, impotence, cerebraland coronary spasm and Raynaud's disease; inflammatory and immunologicaldisease including inflammatory bowel disease, rheumatoid arthritis,graft rejection, asthma, chronic obstructive pulmonary disease, cysticfibrosis and atherosclerosis; cell poliferative disorders includingrestenosis and cancer (including leukemia); disorders of the auditorysystem; disorders of the visual system including macular degenerationand cataracts; diabetes including diabetic retinopathy, diabeticnephropathy and diabetic neuropathy; muscle disease including myotoniaand wasting; peripheral neuropathy; cognitive disorders; migraine;memory loss including Alzheimer's and dementia; CNS mediated motordysfunction including Parkinson's disease, and ataxia; epilepsy; andother ion channel mediated disorders.

As inhibitors of the K_(v)1 subfamily of voltage-gated K⁺ channelscompounds of the present invention are useful to treat a variety ofdisorders including resistance by transplantation of organs or tissue,graft-versus-host diseases brought about by medulla ossiumtransplantation, rheumatoid arthritis, systemic lupus erythematosus,hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes uveitis, juvenile-onset or recent-onset diabetes mellitus,posterior uveitis, allergic encephalomyelitis, glomerulonephritis,infectious diseases caused by pathogenicmicroorganisms, inflammatory andhyperproliferative skin diseases, psoriasis, atopical dermatitis,contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis,lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa,urticaria, angioedemas, vasculitides, erythemas, cutaneouseosinophilias, Lupus erythematosus, acne, alopecia areata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal bums and leukotriene B₄-mediateddiseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis,eczema, interstitial nephritis, Good-pasture's syndrome,hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis,Guillain-Barre syndrome, Meniere's disease, polyneuritis, multipleneuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow'sdisease, pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia osses dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy; Pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenis, metastatis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C₄ release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis sclerosing cholangitis, partial liver resection, acuteliver necrosis, necrosis caused by toxin, viral hepatitis, shock, oranoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholiccirrhosis, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, augention ofchemotherapeutic effect, cytomegalovirus infection, HCMV infection,AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The compounds of the present invention are antiarrhythmic agents whichare useful in the prevention and treatment (including partialalleviation or cure) of arrhythmias. As inhibitors of K_(v)1.5 compoundswithin the scope of the present invention are particularly useful in theselective prevention and treatment of supraventricular arrhythmias suchas atrial fibrillation, and atrial flutter. By “selective prevention andtreatment of supraventricular arrhythmias” is meant the prevention ortreatment of supraventricular arrhythmias wherein the ratio of theprolongation of the atrial effective refractory period to theprolongation of the ventricular effective refractory period is greaterthan 1:1. This ratio is preferably greater than 4:1, more preferablygreater than 10:1, and most preferably such that prolongation of theatrial effective refractory response period is achieved withoutsignificantly detectable prolongation of the ventricular effectiverefractory period.

In addition, the compounds within the scope of the present inventionblock I_(Kur), and thus may be useful in the prevention and treatment ofall I_(Kur)-associated conditions. An “I_(Kur)-associated condition” isa disorder which may be prevented, partially alleviated or cured by theadministration of an I_(Kur) blocker. The Kv1.5 gene is known to beexpressed in stomach tissue, intestinal/colon tissue, the pulmonaryartery, and pancreatic beta cells. Thus, administration of an I_(Kur)blocker could provide useful treatment for disorders such as: refluxesauphagitis, functional dispepsia, constipation, asthma, and diabetes.Additionally, Kv1.5 is known to be expressed in the anterior pituitary.Thus, administration of an I_(Kur) blocker could stimulate growthhormone secretion. I_(Kur) inhibitors can additionally be useful in cellpoliferative disorders such as leukemia, and autoimmune diseases such asrheumatoid arthritis and transplant rejection.

The present invention thus provides methods for the prevention ortreatment of one or more of the aforementioned disorders, comprising thestep of administering to a subject in need thereof an effective amountof at least one compound of the formula I. Other therapeutic agents suchas those described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I or saltsthereof capable of preventing or treating one or more of theaforementioned disorders in an amount effective therefor, and apharmaceutically acceptable vehicle or diluent. The compositions of thepresent invention may contain other therapeutic agents as describedbelow, and may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavors,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrastemal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. In the case where the compounds of formula Iare being administered to prevent or treat arrhythmias, the compoundsmay be administered to achieve chemical conversion to normal sinusrhythm, or may optionally be used in conjunction with electricalcardioconversion.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I may also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders or otherdisorders, including: other antiarrhythmic agents such as Class I agents(e.g., propafenone), Class II agents (e.g., carvadiol and propranolol),Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide andibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HTantagonists (e.g., sulamserod, serraline and tropsetron), anddronedarone; calcium channel blockers (both L-type and T-type) such asdiltiazem, verapamil, nifedipine, amlodipine and mybefradil;Cyclooxygenase inibitors (i.e., COX-1 and/or COX-2 inhibitors) such asaspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxxand NSAIDs; anti-platelet agents such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide and tirofiban), P2Y₁₂ antagonists (e.g.,clopidogrel, ticlopidine and CS-747), thromboxane receptor antagonists(e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole)with or without aspirin; diruetics such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride, andspironolactone; anti-hypertensive agents such as alpha adrenergicblockers, beta adrenergic blockers, calcium channel blockers, diuretics,renin inhibitors, ACE inhibitors, (e.g., captropril, zofenopril,fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril,quinapril, ramipril, lisinopril), A II antagonists (e.g., losartan,irbesartan, valsartan), ET antagonists (e.g. sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), nitrates, andcombinations of such anti-hypertensive agents;antithrombotic/thrombolytic agents such as tissue plasminogen activator(tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, factor Xa inhibitors, thromin inibitors (e.g., hirudinand argatroban), PAI-1 inhibitors (i.e., inactivators of tissueplasminogen activator inhibitors), α2-antiplasmin inhibitors,streptokinase, urokinase, prourokinase, anisoylated plasminogenstreptokinase activator complex, and animal or salivary glandplasminogen activators; anticoagulants such as warfarin and heparins(including unfractionated and low molecular weight heparins such asenoxaparin and dalteparin); HMG—CoA reductase inhibitors such aspravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin); other cholesterol/lipidlowering agents such as squalene synthetase inhibitors, fibrates, andbile acid sequestrants (e.g., questran); antipoliferative agents such ascyclosporin A, taxol, FK 506, and adriamycin; antitumor agents such astaxol, adriamycin, epothilones, cisplatin and carboplatin; anti-diabeticagents such as biguanides (e.g. metformin), glucosidase inhibitors (e.g.acarbose), insulins, meglitinides (e.g. repaglinide), sulfonylureas(e.g. glimepiride, glyburide and glipizide), biguanide/glyburidecombinations (i.e,. glucovance), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), PPAR-gamma agonists, aP2 inhibitors,and DP4 inhibitors; thyroid mimetics (including thyroid receptorantagonists) (e.g., thyrotropin, polythyroid, KB-130015, anddronedarone); Mineralocorticoid receptor antagonists such asspironolactone and eplerinone; growth hormone secretagogues;anti-osteoporosis agents (e.g., alendronate and raloxifene); hormonereplacement therapy agents such as estrogen (including conjugatedestrogens in premarin), and estradiol; antidepressants such asnefazodone and sertraline; antianxiety agents such as diazepam,lorazepam, buspirone, and hydroxyzine pamoate; oral contraceptives;anti-ulcer and gastroesophageal reflux disease agents such asfamotidine, ranitidine, and omeprazole; anti-obesity agents such asorlistat; cardiac glycosides including digitalis and ouabain;phosphodiesterase inibitors including PDE III inhibitors (e.g.cilostazol), and PDE V inhibitors (e.g., sildenafil); protein tyrosinekinase inhibitors; steroidal anti-inflammatory agents such asprednisone, and dexamethasone; and other anti-inflammatory agents suchas enbrel.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Assays to determine the degree of activity of a compound as an I_(Kur)inhibitor are well known in the art and are described in references suchas J. Gen. Physiol. April; 101(4):513-43, and Br. J. Pharmacol. 1995May; 115(2):267-74.

Assays to determine the degree of activity of a compound as an inhibitorof other members of the K_(v)1 subfamily are also well known in the art.For example, inhibition of Kv1.1, K_(v)1.2 and K_(v)1.3 can be measuredusing procedures described by Grissmer S, et al., Mol Pharmacol 1994June; 45(6):1227-34. Inhibition of Kv1.4 can be measured usingprocedures described by Petersen K R, and Nerbonne J M, Pflugers Arch1999 February; 437(3):381-92. Inhibition of Kv1.6 can be measured usingprocedures described by Bowlby M R, and Levitan I B, J Neurophysiol 1995June; 73(6):2221-9. And inhibition of Kv1.7 can be measured usingprocedures described by Kalman K, et al., J Biol Chem 1998 Mar. 6;273(10):5851-7.

Compounds within the scope of the present invention demonstrate activityin K_(v)1 assays such as the ones described above.

All documents cited in the present specification are incorporated hereinby reference in their entirety.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It is to be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto.

EXAMPLE 1

Cis andTrans-N-(4-Hydroxy-1-thiophen-2-yl-cyclohexylmethyl)-2-methoxy-benzamide

Synthesis:

Compound 2: Triton B (0.19 mL, 40% by weight solution in methanol, 0.42mmol) was added to a solution of 2-thiophene acetonitrile (500 mg, 4.06mmol) in acetonitrile (27 mL) at room temperature. The reaction mixturewas heated under nitrogen to 95° C. and methylacrylate (3.6 mL, 40 mmol)was added slowly (vigorous exotherm). After 5 h, the reaction mixturewas allowed to cool and diluted with 50 mL of ether. The solution wastransferred to a separation funnel and washed successively with HCl (1N,2×20 mL) and saturated NaCl (1×20 mL). The organic portion was driedover anhydrous Na₂SO₄, decanted and concentrated yielding 1.10 g (92%crude yield) of 2 as a dark brown oil ¹H NMR (CDCl₃) 2.2 ppm, 2H,multiplet; 2.3 ppm, 2H, multiplet; 2.4 ppm, 2H, multiplet; 3.65 ppm, 6H,singlet; 6.97 ppm, 1H, dd, J=3.6 and 6.2 Hz; 7.13 ppm, 1H, dd, J=1.2 and3.6 Hz; 7.32 ppm, 1H, dd, J=1.2 and 5.1 Hz.

Compound 3: Compound 2 (1.10 g, 3.72 mmol) was dissolved in anhydrousdimethylethylene glycol (20 mL). Sodium hydride (60% dispersion inmineral oil, 360 mg, 11.2 mmol) was added slowly to the solution and theresulting brown slurry was heated under nitrogen to 95° C. for 4.5 hthen allowed to cool overnight (12 h). The slurry was poured carefullyinto 15 mL of water and diluted with 100 mL ether. The organic portionwas washed with HCl (3.7N, 2×20 mL), dried over anhydrous Na₂SO₄,decanted and concentrated yielding a brown oil. The crude oil waspurified by silica gel flash chromatography elution with 3:1hexane:ethylacetate yielding 298 mg (31% isolated yield) of 3 as a palebrown oil. HPLC Rt 3.10 min, Purity 100%, YMC S5 column 4.6×50 mm, 4 mingradient 0 to 100% MeOH (90% in water, 0.2% H₃PO₄) UV detection at 220nm. LCMS Rt 1.61 min, [M+Na] 286.10 YMC S5 column 4.6×30 mm, 2 mingradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm.¹H NMR (CDCl₃) 2.2 ppm, 2H, multiplet; 2.4ppm, 2H, multiplet; 2.7ppm,2H, multiplet; 2.75 ppm, 1H, d, J=13.6 Hz; 3.15 ppm, 1H, d, J=15.0 Hz;7.00 ppm, 1H, dd, J=3.6 and 5.1 Hz; 7.18 ppm, 1H, dd, J=1.2 and 3.6 Hz;7.29 ppm, 1H, dd, J=1.2 and 5.2 Hz; 12.2 ppm, 1H, singlet.

Compound 4: To a solution of P-keto ester 3 (298 mg, 1.13 mmol) in DMSO(8 mL containing 0.5 mL water) was added NaCl (420 mg, 7.24 mmol). Thereaction mixture was heated to 150° C. for 5 h then allowed to cool toambient temperature. The solution was diluted with 1:1 ether:ethylacetate (50 mL), transferred to a separation funnel and washed with10% LiCl (3×20 mL). The organic portion was dried over anhydrous Na₂SO₄,decanted and concentrated yielding 4 as a pale brown powder sufficientlypure to be used in the next step, (184 mg, 80% yield). HPLC Rt 2.36 min,Purity 97%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90%in water, 0.2% H₃PO₄) UV detection at 220 nm. ¹H NMR (CDCl₃) 2.3ppm, 2H,multiplet; 2.6 ppm, 4H, multiplet; 2.9 ppm, 2H, multiplet; 7.00 ppm, 1H,dd, J=3.6 and 6.2 Hz; 7.20 ppm, 1H, dd, J=1.2 and 3.6 Hz; 7.32 ppm, 1H,dd, J=1.2 and 5.1 Hz.

Compound 5: was dissolved in toluene (2 mL) and ethylene glycol (0.54mL, 9.6 mmol) and toluene sulfonic acid (9 mg, 0.05 mmol) added. Thesolution was heated to reflux with Dean-Stark azeotropic removal ofwater for 14 h. The cooled reaction mixture was diluted with ether (100mL) and washed with water (3×20 mL). The organic portion was dried overanhydrous Na₂SO₄, decanted and concentrated yielding 5 as a pale brownoil, (323 mg, crude quantative yield). HPLC Rt 2.90 min, Purity 83.0%,YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water,0.2% H₃PO₄) UV detection at 220 nm. ¹H NMR (CDCl₃) 1.9 ppm, 2H,multiplet; 2.0 ppm, 2H, multiplet; 2.1 ppm, 2H, multiplet; 2.2 ppm, 2H,multiplet; 4.00 ppm, 4H, multiplet; 6.98 ppm, 1H, dd, J=1.2 and 3.6 Hz;7.14 ppm, 1H, dd, J=1.2 and 5.1 Hz; 7.27 ppm, 1H, dd, J=1.2 and 5.1 Hz.

Compound 6: At ambient temperature a solution of LiAlH₄ (1.0M in THF,1.35 mL, 1.35 mmol) was added to a solution of 5 in THF (5 mL). Theresulting slurry was heated to reflux under nitrogen for 3 h then cooledto 0° C. 1N NaOH (0.3 mL) was added dropwise and after 10 min ofvigorous stirring, anhydrous Na₂SO₄ was added. The slurry was filteredthrough a glass frit and the filter washed with THF, then the filtrateconcentrated to yield 151 mg (66% yield) of 6 as a colorless oil. HPLCRt 1.47 min, Purity 98%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to100% MeOH (90% in water, 0.2% H₃PO₄) UV detection at 220 nm. ¹H NMR(CDCl₃) 1.7 ppm, 4H, multiplet; 1.8 ppm, 2H, multiplet; 2.1 ppm, 2H,multiplet; 2.7 ppm, 2H, multiplet; 3.92, 4H, multiplet; 6.86, 1H, dd,J=0.9 and 3.5 Hz; 6.97, 1H, dd, J=3.5 and 5.0 Hz; 7.21, 1H, dd, J=0.9and 5.0 Hz.

Compound 7 At ambient temperature ortho-anisoyl chloride (107 mg, 0.597mmol) was added to a solution of amine 6 in dichloromethane (2 mL) andTEA (63 mg, 0.63 mmol). The resulting pale yellow solution was stirredfor 1 h then loaded directly onto a silica gel chromatography column.The column was eluted with 1:1 hexane:ethylacetate to provide 195 mg(85% yield) of the amide 7 as a colorless oil. HPLC Rt 3.34 min, Purity97%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% inwater, 0.2% H₃PO₄) UV detection at 220 nm. LCMS Rt 1.73 min, [M+1]388.13 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% inwater, 0.1% TFA) UV detection at 220 nm. ¹H NMR (CDCl₃) 1.7 ppm, 4H,multiplet; 2.0 ppm, 2H, multiplet; 2.2 ppm, 2H, multiplet; 3.68 ppm, 2H,d, J=6.0 Hz; 3.73, 3H, s; 4.1 ppm, 4H, multiplet; 6.89 ppm, 1H, d, J=8.3Hz; 6.95 ppm, 1H, dd, J=0.9 and 3.5 Hz; 7.01 ppm, 1H, dd, J=3.5 and 5.1Hz; 7.06 ppm, 1H, dd, J=7.4 and 8.0 Hz; 7.27 ppm, 1H, dd, J=0.8 and 4.9Hz; 7.40 ppm, 1H, dd, J=1.1 and 1.7 Hz; 7.8 ppm, 1H, br s; 8.19 ppm, 1H,dd, J=1.8 and 7.8 Hz.

Compound 8: (195 mg, 0.504 mmol) was dissolved in THF (4 mL) and 2N HClwas added (1 mL). The resulting solution was heated to 40° C. for 3 h,allowed to cool, diluted with ether (50 mL) and washed with sat. NaHCO₃(3×20 mL). The organic portion was dried over anhydrous Na₂SO₄, decantedand concentrated yielding 200 mg (crude quantative yield) of 9 as acolorless oil. HPLC Rt 3.00 min, Purity 92%, YMC S5 column 4.6×50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0.2% H₃PO₄) UV detection at220 nm. LCMS Rt 1.55 min, [M+1] 333.08 YMC S5 column 4.6×30 mm, 2 mingradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm.¹H NMR (CDCl₃) 2.2 ppm, 2H, multiplet; 2.5 ppm, 6H, multiplet; 3.75, 3H,s; 3.79 ppm, 1H, d, J=6.2 Hz; 6.92 ppm, 1H, d, J=8.3 Hz; 7.03 ppm, 1H,dd, J=0.9 and 3.5 Hz; 7.08 ppm, 2H, multiplet; 7.35 ppm, 1H, dd, J=0.8and 5.1 Hz; 7.43 ppm, 1H, ddd, J=1.8, 7.5 and 8.5 Hz; 7.9 ppm, 1H, br t;8.20 ppm, 1H, dd, J=1.8 and 7.8 Hz.

Compounds 9 and 10: To a solution of crude ketone 8 (200 mg crude, 0.504mmol) in THF (4 mL) was added NaBH₄ (44 mg, 1.5 mmol). The reactionmixture was stirred at ambient temperature under nitrogen for 14 h thenthe slurry diluted with dichloromethane (100 mL). The slurry wastransferred to a separatory funnel and the organic portion washed with1N HCl (2×20 mL), dried over anhydrous Na₂SO₄, decanted and concentratedyielding a mixture of 9 and 10 as a colorless oil. The isomers wereseparated by preparative thin layer chromatography (25×25 cm, lmm platewith UV indicator at 254 nm) using 2:1 dichloromethane:MTBE as eluent.Compound 9 (43 mg) was isolated as the less polar constituent: HPLC Rt3.16 min, Purity 95%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100%MeOH (90% in water, 0.2% H₃PO₄) UV detection at 220 nm. LCMS Rt 1.64min, [M+1] 346.10 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH(90% in water, 0.1% TFA) UV detection at 220 nm. ¹H NMR (MeOD) 1.3 ppm,2H, multiplet; 1.5 ppm, 2H, multiplet; 2.1 ppm, 2H, br d; 3.37 ppm, 2H,s; 3.5 ppm, 1H, multiplet; 3.64 ppm, 3H, s; 6.8 ppm, 4H, multiplet; 7.22ppm, 1H, dd, J=0.7 and 5.4 Hz; 7.32 ppm, 1H, dd, J=1.8 and 8.7 Hz; 7.78ppm, 1H, dd, J=1.7 and 7.8 Hz; 8.0 ppm, 1H, br s. Compound 10 (47 mg)was isolated as the more polar constituent: HPLC Rt 2.95 min, Purity94%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% inwater, 0.2% H₃PO₄) UV detection at 220 nm. LCMS Rt 1.52 min, [M+1]346.13 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90% inwater, 0.1% TFA) UV detection at 220 nm. ¹H NMR (MeOD) 1.6 ppm, 4H,multiplet; 1.8 ppm, 2H, multiplet; 2.0 ppm, 2H, multiplet; 3.62 ppm, 1H,d, J=5.9 Hz; 3.63, 1H, br multiplet; 3.64 ppm, 3H, s; 6.9 ppm, 4H,multiplet; 7.26 ppm, 1H, dd, J=0.6 and 4.6 Hz; 7.36 ppm, 1H, dd, J=1.8and 8.7 Hz; 7.87 ppm, 1H, dd, J=1.8 and 7.8 Hz; 8.0 ppm, 1H, br t.

EXAMPLES 2-12

Examples 2 to 12 were prepared using methodology described in Example 1.Ex. Structure Name [M + 1] 2

N-(4-Hydroxy-1- thiophen-3-yl- cyclohexylmethyl)- 2-methoxy- benzamide346 3

N-(4-Hydroxy-1- thiophen-3-yl- cyclohexylmethyl)- 2-methoxy- benzamide346 4

N-[1-(3-Ethyl-5- methyl-isoxazol-4- yl)-4-hydroxy- cyclohexylmethyl]-2-methoxy- benzamide 373 5

N-(1- Benzo[b]thiophen-3- yl-4-hydroxy- cyclohexylmethyl]- 2-methoxy-benzamide 396 6

N-(1- Benzo[b]thiophen-3- yl-4-hydroxy- cyclohexylmethyl]- 2-methoxy-benzamide 396 7

2,5-Dimethyl-furan- 3-carboxylic acid (1- benzo[b]thiophen-3-yl-4-hydroxy- cyclohexylmethyl)- amide 384 8

2,5-Dimethyl-furan- 3-carboxylic acid (1- benzo[b]thiophen-3-yl-4-hydroxy- cyclohexylmethyl)- amide 384 9

5-Chloro-4-methoxy- thiophene-3- carboxylic acid (1- benzo[b]thiophen-3-yl-4-hydroxy- cyclohexylmethyl)- amide 437 10

5-Chloro-4-methoxy- thiophene-3- carboxylic acid (1- benzo[b]thiophen-3-yl-4-hydroxy- cyclohexylmethyl)- amide 437 11

Pyridine-2- carboxylic acid (1- benzo[b]thiophen-3- yl-4-hydroxy-cyclohexylmethyl)- amide 367 12

Pyridine-2- carboxylic acid (1- benzo[b]thiophen-3- yl-4-hydroxy-cyclohexylmethyl)- amide 367

EXAMPLE 13

Trans-Ethyl-carbamic acid4-[(2-methoxy-benzoylamino)-methyl]-4-thiophen-2-yl-cyclohexyl ester

Synthesis:

Compound 1 The synthesis of 1 is described in Example 1.

Compound 2: At ambient temperature 4-nitrophenylchloroformate (45 mg,0.22 mmol) was added to a solution of alcohol 1 (43 mg, 0.12 mmol) indichloromethane (10 mL) containing triethylamine (ca. 38 mg). Theresulting yellow solution was stirred for 72 h then purified directly bysilica gel chromatography elution with 2:1 hexane:ethylacetate yielding32 mg (52% yield) of 2 as a colorless oil. HPLC Rt 3.91 min, Purity 84%,YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water,0.2% H₃PO₄) UV detection at 220 nm. ¹H NMR (CDCl₃) 1.8 ppm, 4H,multiplet; 2.1 ppm, 2H, multiplet; 2.3 ppm, 2H, multiplet; 3.69 ppm, 1H,d, J=6.0 Hz; 3.75 ppm, 3H, s; 4.8 ppm, 1H, multiplet; 6.9 ppm, 3H,multiplet; 7.05 ppm, 2H, multiplet; 7.32 ppm, 1H, d, J=8.0 Hz; 7.45 ppm,1H, dd, J=1.8 and 8.7 Hz; 7.9 ppm, 1H, brt; 8.15 ppm, 1H, d, J=8.0 Hz;8.20 ppm, 1H, dd, J=1.8 and 7.8 Hz.

Compound 3: A solution of ethylamine (0.8 mL, 2.0M in THF) was added toa solution of 2 (32 mg, 0.062 mmol) in dichloromethane (3 mL) at ambienttemperature. After 1 h the yellow solution was loaded directly onto apreparative thin layer chrmoatography plate (25×25 cm, lmm with UVindicator at 254 nm). The plate was eluted using 1:1 hexane:ethylacetateto provide 1 lmg (43% yield) of 3 as a colorless glass. HPLC Rt 3.37min, Purity 96%, YMC S5 column 4.6×50 mm, 4 min gradient 0 to 100% MeOH(90% in water, 0.2% H₃PO₄) UV detection at 220 nm. LCMS Rt 1.71 min,[M+1] 417.14 YMC S5 column 4.6×30 mm, 2 min gradient 0 to 100% MeOH (90%in water, 0.1% TFA) UV detection at 220 nm. ¹H NMR (CDCl₃) 1.09 ppm, 3H,t, J=7.1 Hz; 1.6 ppm, 2H, multiplet; 1.8 ppm, 2H, multiplet; 2.0 ppm,2H, multiplet; 2.2 ppm, 2H, multiplet; 3.18 ppm, 2H, multiplet; 3.65ppm, 2H, d, J=6.0 Hz; 3.74 ppm, 3H, s; 4.72 ppm, 1H, br s; 4.48 ppm, 1H,br s; 6.90 ppm, 1H, d, J=8.2 Hz; 6.95 ppm, 1H, d, J=3.0 Hz; 7.15 ppm,2H, multiplet; 7.28 ppm, 1H, d, J=5.0 Hz; 7.45 ppm, 1H, dd, J=1.8 and8.8 Hz; 7.8 ppm, 1H, br s; 8.20 ppm, 1H, d, J=2.2 and 7.7 Hz.

EXAMPLES 14-27

Examples 14 to 27 were prepared using methodology described in Example13. Ex. Structure Name [M + 1] 14

Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)- methyl]-4-thiophen-2-yl-cyclohexyl ester 417 15

Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)- methyl]-4-thiophen-2-yl-cyclohexyl ester 417 16

Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)- methyl]-4-thiophen-3-yl-cyclohexyl ester 417 17

Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)- methyl]-4-thiophen-3-yl-cyclohexyl ester 417 18

Ethyl-carbamic acid 4- (3-ethyl-5-methyl- isoxazol-4-yl)-4-[(2- methoxy-benzoylamino)- methyl]-cyclohexyl ester 444 19

Ethyl-carbamic acid 4- (3-ethyl-5-methyl- isoxazol-4-yl)-4-[(2- methoxy-benzoylamino)- methyl]-cyclohexyl ester 444 20

Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-[(2-methoxy-benzoylamino)- methyl]-cyclohexyl ester 467 21

Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-[(2-methoxy-benzoylamino)- methyl]-cyclohexyl ester 467 22

Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)- methyl]-4-pyridin-2-yl-cyclohexyl ester 412 23

Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)- methyl]-4-pyridin-2-yl-cyclohexyl ester 455 24

Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-{[(2,5-dimethyl-furan-3-carbonyl)- amino]-methyl}- cyclohexyl ester 455 25

Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-{[(2,5-dimethyl-furan-3-carbonyl)- amino]-methyl}- cyclohexyl ester 507 26

Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-{[(5-chloro-4-methoxy-thiophene-3- carbonyl)-amino]- methyl}-cyclohexyl ester 507 27

Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-{[(5-chloro-4-methoxy-thiophene-3- carbonyl)-amino]- methyl}-cyclohexyl ester 418

EXAMPLE 28

Acetic acid4[(2-methoxy-benzoylamino)-methyl]-4-thiophen-3-yl-cyclohexyl ester

Synthesis:

Compound 1: The synthesis of 1 is described in Example 1.

Compound 2: At ambient temperature acetyl chloride (6 mg, 0.08 mmol) wasadded to a solution of alcohol 1 (14 mg, 0.040 mmol) in dichloromethane(10 mL) containing TEA (ca. 8 mg). The resulting yellow solution wasstirred for 16 h then purified directly by preparative HPLC YMC ODS S520×100 mm column 30-100% MeOH (90% in water, 0.1% TFA) gradient over 8min with flow rate 20 mL/min and UV detection at 220 nm. The ester 2eluted at a retention time of 8.6 min. and was isolated as a colorlessoil (6.6 mg, yield 43%). HPLC Rt 3.42 min, Purity 100%, YMC S5 column4.6×50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2% H₃PO₄) UVdetection at 220 nm. LCMS Rt 1.78 min, [M+1] 388.13 YMC S5 column 4.6×30mm, 2 min gradient 0 to 100% MeOH (90% in water, 0.1% TFA) UV detectionat 220 nm. ¹H NMR (CDCl₃) 1.7 ppm, 2H, multiplet; 1.8 ppm, 2H,multiplet; 1.9 ppm, 4H, multiplet; 2.06 ppm, 3H, s; 3.71 ppm, 3H, s;3.71 ppm, 2H, d, J=8.0 Hz; 5.3 ppm, 1H, septet; 6.90 ppm, 1H, d, J=8.3Hz; 7.06 ppm, 1H, t; 7.1 ppm, 2H, multiplet; 7.4 ppm, 2H, multiplet;7.74 ppm, 1H, br t; 8.19 ppm, 1H, dd, J=1.8 Hz and 7.8 Hz.

EXAMPLES 29-30

Examples 29 to 30 were synthesized using methodology described inExample 28. Ex. Structure Name [M + 1] 29

Butyric acid 4-[(2- methoxy- benzoylamino)- methyl]-4-thiophen-3-yl-cyclohexyl ester 416 30

Butyric acid 4-[(2- methoxy- benzoylamino)- methyl]-4-thiophen-3-yl-cyclohexyl ester 416

EXAMPLE 31

cis-2-Methoxy-N-[4-(N-methyl-N′-cyanoguanidino)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: To a solution of 4-phenyl-4-cyano-cyclohexane-1-one 1 (10 g,50 mmol) in 200 ml of toluene was added p-toluenesulfonic acidmonohydrate (2.5 g, 13.1 mmol) and ethylene glycol (20 ml, 360 mmol) ina portion, respectively. The resulting solution was stirred at refluxfor 5 h. The reaction mixture was concentrated in vacuo to yield oilyresidue. It was then diluted with EtOAc (200 ml) and washed with aq.NaHCO₃ (50 ml×2) and brine (50 ml×1). The organic layer was dried overMgSO₄ and concentrated in vacuo to provide an oil (12.9 g, >95%), whichwas subjected to the following reaction without any furtherpurification.

Compound 3: Into a solution of the nitrile 2 (12.9 g) in 100 ml of THFwas added 60 ml of 1M LAH/THF dropwide and the resulting solution wasstirred at reflux for 2 h. The reaction mixture was cooled to 0° C. andquenched carefully with water. The reaction mixture was diluted withEtOAc (500 ml) and washed with aq. LiOH−NaCl (50 ml×3). The organiclayer was dried over MgSO₄ and concentrated in vacuo to provide an oil(13.6 g, >95%), which was subjected to the following reaction withoutfurther purification.

Compound 4: To a solution of amine 3 (5.9 g, 24 mmol) and Et₃N (6.0 ml,43 mmol) in 100 ml of CH₂Cl₂ was added anisoyl chloride (4.5 ml, 30.4mmol) dropwise at 0° C. and the resulting solution was stirred for 2 h.The reaction mixture was concentrated in vacuo, yielding a white solidresidue which was partitioned between EtOAc (200 ml) and aq. NaHCO₃ (50ml). The organic layer was dried over MgSO₄ and concentrated in vacuo toprovide an oil, which was diluted in 50 ml of THF and 50 ml of 2N aq.HCl. The resulting solution was stirred for 12 h at 25° C. The reactionmixture was diluted with EtOAc (200 ml). The organic layer wasseparated, washed with brine (50 ml×2), and dried over MgSO₄.Concentration of the organic layer produced an oily residue, which waspurified on column chromatography (50% EtOAc/Hex) to yield 6.8 g (20.2mmol, 84% for two steps) of the desired product.

Compound 5: To a solution of the ketone 4 (13 g, 38.6 mmol) in 100 ml ofMeOH was added NH4OAc (23.2 g, 300 mmol) and NaBH(OAc)₃ (12.2 g, 57.8mmol) and the resulting mixture was stirred for 12 h at 25° C. Thereaction mixture was concentrated in vacuo to produce a solid residue,which was partitioned between EtOAc (200 ml) and IN aq. NaOH (30 ml×2).The organic layer was dried over MgSO₄. Concentration of the organicsolution provided oily residue, which was subjected to columnchromatography (10% NH₃—MeOH/CH₂Cl₂) to obtain 10.8 g of the desiredproduct as 1:1 mixture of two diastereoisomers.

Compounds 6 and 7: The amine 5 (3.6 g, 10.7 mmol) was dissolved in CH₃CN(100 ml). A solution of di-tert-butyldicarbonate (3.5 g, 16 mmol)dissolved in 30 ml of CH₃CN was added dropwise. The mixture was stirredfor 2 h at 25° C. Reaction mixture was concentrated in vacuo to providean oily residue, which was subjected to column chromatography (50%Hex/EtOAc) to yeild 2.1 g of trans-isomer (retention time: 2.43 min) and1.9 g of the cis-isomer (retention time: 2.67 min)of the boc-protectedamine. Each of the amines were dissolved in 40 ml of 25% TFA/CH₂Cl₂ andstirred at 25° C. for 2 h. They were concentrated in vacuo to provideoily residues, which were dissolved in EtOAc (150 ml, respectively) andwashed with 1N aq. NaOH (100 ml×2). The organic layers were dried overMgSO₄ and concentrated in vacuo to provide an oil, which corresponds tothe amine of a single diastereoisomer.

Compound 9: To a solution of the cis-isomer of the amine 6 (700 mg, 2.07mmol) in 40 ml of 2-propanol was added diphenyl cyanocarbonimidate (0.48g, 2.07 mmol) and the reaction mixture was stirred at reflux for 4 h. Itwas concentrated in vacuo to provide an oil, which was used in afollowing reactions without any further purification.

Compound 10: To a solution of 9 (100 mg, 0.21 mmol) in 2 ml of2-propanol was added 2 ml of MeNH₂ (2N in THF). The mixture was stirredfor 2 h at 75° C. in a sealed tube. The reaction mixture was cooled toroom temperature and concentrated in vacuo to provide oily residue,which was purified by preparative HPLC (YMC S5 ODS 30×250 mm reversephase column; 30 min gradient from 70:30 A:B to 100% B, where solventA=90:10:0.1 H₂O: MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) toprovide 53.4 mg (0.13 mmol, 62%) of the desired product as a white solidafter lyophilization (MeOH/H₂O). [M+H]=420.

EXAMPLES 32-52

Examples 32 to 52 were synthesized using methodology described inExample 31. Ex. Structure Name (M + H) 32

cis-2-Methoxy-N- [4-(N-benzyl-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 496 33

cis-2-Methoxy-N- [4-(N,N-diethyl- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 462 34

cis-2-Methoxy-N- [4-(N,N-dipropyl- N′-cyano- guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 490 35

cis-2-Methoxy-N- [4-(N-propyl-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 448 36

cis-2-Methoxy-N- [4-(N-ethyl-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 434 37

cis-2-Methoxy-N- [4-(N-hexyl-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 490 38

cis-2-Methoxy-N- [4-(N-methyl-N- benzyl-N′-cyano- guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 510 39

cis-2-Methoxy-N- [4-(N-tert-butyl-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 462 40

cis-2-Methoxy-N- [4-(N- cyanoguanidino)-1- phenyl-cyclohexyl-methyl]-benzamide 406 41

cis-2-Methoxy-N- [4-(N-acetonitrilo- N′-cyano- guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 445 42

cis-2-Methoxy-N- [4-(azetidinyl-N- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 446 43

cis-2-Methoxy-N- [4-(N-cyclopropyl- N′-cyano- guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 446 44

cis-2-Methoxy-N- [4-(N-(2- hydroxyethyl)-N′- cyano-guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 450 45

cis-2-Methoxy-N- [4-(N-allylic-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 446 46

cis-N-{4-[N′- hydroxy-1-methyl- ethyl)-N″- cyanoguanidino]-1-phenyl-cyclohexyl- methyl}-2-methoxy- benzamide 464 47

cis-2-Methoxy-N- [4-(N-prop-2-ylnyl- N′-cyano- guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 444 48

cis-2-Methoxy-N- [4-(N- cyclopropylmethyl- N′-cyano- guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 460 49

cis-2-Methoxy-N- [4-(pyrrolidinyl-N- cyano-guanidino)-1-phenyl-cyclohexyl- methyl]benzamide 460 50

cis-2-Methoxy-N- [4-(N-methoxy-N′- cyano-guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 436 51

cis-2-Methoxy-N- [4-(N-methylamino- N′-cyano- guanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 435 52

cis-2-Methoxy-N- [4-(N,N-dimethyl- N′-cyano- guanidino)-1- phenyl-cyclohexylmethyl]- benzamide 434

EXAMPLE 53

trans-2-Methoxy-N-[4-(N-methyl-N′-cyanoguanidino)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1: compound 1 was synthesized as described in Example 31.

Compound 2: To a solution of the trans-amine 1 (300 mg, 1.26 mmol) in 20ml of 2-propanol was added diphenyl cyanocarbonidate (0.24 g, 1.26 mmol)and the resulting mixture was stirred at reflux for 4 h. The reactionmixture was concentrated in vacuo to provide an oil, which was used in afollowing reaction without any further purification.

Compound 3: To solution of intermediate 2 (100 mg, 0.21 mmol) in 2 ml of2-propanol was added 2 ml of methylamine (2N in THF). The mixture wasstirred for 2 h at 75° C. in a sealed tube. The reaction mixture wascooled down and concentrated in vacuo to provide oily residue, which waspurified by preparative HPLC (described in Example 1) to provide 49.3 mg(0.12 mmol, 57%) of the desired product as a white solid afterlyophilization (MeOH/H20). [M+H]=420.

EXAMPLES 54-61

Examples 54 to 61 were synthesized using methodology described inExample 53. Ex. Structure Name (M + H) 54

trans-2-Methoxy-N-[4- (N-benzyl-N′- cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 434 55

trans-2-Methoxy-N-[4- (N,N-diethyl-N′- cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 490 56

trans-2-Methoxy-N-[4- (N,N-dipropyl-N′- cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 510 57

trans-2-Methoxy-N-[4- (N-propyl-N′- cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 462 58

trans-2-Methoxy-N-[4- (N-ethyl-N′- cyanoguanidino)-1- phenyl-cyclohexyl-methyl]-benzamide 434 59

trans-2-Methoxy-N-[4- (N-n-hexyl-N′- cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 490 60

trans-2-Methoxy-N-[4- (N-methyl-N-benzyl- N′-cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide  10 61

trans-2-Methoxy-N-[4- (N-tert-butyl-N′- cyanoguanidino)-1-phenyl-cyclohexyl- methyl]-benzamide 462

EXAMPLE 62 AND 63

trans andcis-N-[4-(N,N′-Diethyl-cyanoguanidino)-1-phenyl-1-cyclohexylmethyl]-2-methoxy-benzamide

Compound 1: The synthesis of 1 is described in example 31.

Compound 2: To a solution of the ketone 1 (0.34 g, 1 mmol) in 35 ml ofdichloromethane was addded EtNH₂ (1 ml of 2M solution in THF, 2 mmol),NaBH(OAc)₃ (0.42 g, 2 mmol) and drops of AcOH (cat. amount). Theresulting solution was stirred at 25° C. for 3 h. Reaction mixture wasconcentrated in vacuo yielding oily residue, which was diluted in 250 mlof AcOH and washed with 1N aq. NaOH (20 ml×2). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to provide 2 as an oil (0.35g, >95%), which was subjected to the following reaction without furtherpurification.

Compound 3: A solution of diphenyl cyanocarbonidate (2.4 g, 10 mmol) andEtNH₂ (5 ml of 2M solution in MeOH, 10 mmol) in 10 ml of 2-propanol wasstirred for 4 h at 70° C. in a sealed tube. The reaction mixture wasconcentrated in vacuo yielding a white solid, which was purified oncolumn chromatography (30% EtOAc/Hex) to yield 1.6 g (85%) of thedesired product 3 as a white solid.

Compound 4: A solution of compound 2 (110 mg, 0.3 mmol) and compound 3(74 mg, 0.39 mmol) in 5 ml of 2-propanol was stirred for 12 h at 70° C.The reaction mixture was concentrated and purified on preparative-HPLC(described in a synthesis of Example 31) to provide the cis and transdiastereoisomers. Trans compound (retention time: 3.19 min) (23 mg) andcis compound (retention time: 3036 min) (14 mg) were obtained ascolorless oils. Mass Spec [M+H]⁺ 462.

EXAMPLE 64

trans-2-Methoxy-N-[4-(N-ethyl-N′-sulfenylureido)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1:: The synthesis of 1 was described in Example 31.

Compound 2: Chlorosulfonyl isocyanate (0.37 ml, 4.1 mmmol) was dissolvedin 40 ml of dichloromethane and cooled to 0° C. Chloroethanol (0.27 ml,4.1 mmol) was added slowly and the reaction mixture was stirred foradditional 1.5 h at 0° C. A solution of the amine 1 (1.4 g, 4.1 mmol)and Et₃N (1.3 ml, 12.4 mmol) in 50 ml of dichloromethane was addedslowly into the reaction mixture so that reaction temperature did notexceed 5° C. The reaction mixture was allowed to warm to 25° C. andstirred overnight. The reaction was quenched by dropwise addition of 2NHCl and saturated with NaCl. The organic layer was separated and theaqueous layer was extracted with dichloromethane (100 ml×3). Thecombined organic layer was dried over MgSO₄ and concentrated in vacuo toprovide 2 as a white solid (2.0 g), which was subjected to the followingreactions without further purification.

Compound 3: A solution of 2 (90 mg, 0.18 mmol), EtNH₂ (0.4 mmol, 0.2 mlof 2M solution in MeOH) and Et₃N (0.1 ml) in 2 ml of CH₃CN was stirredfor 2 h at 65° C. The reaction mixture was purified in preparative HPLC(described in the synthesis of Example 31) to yield 12.1 mg of 3 as acolorless oil. Mass Spec [M+H]⁺=446.

EXAMPLES 65-72

Examples 65 to 72 were synthesized using methodology described inExample 64. (M + Ex. Structure Name H) 65

trans-2- Methoxy-N- [4-(N- methyl- N- benzyl-N′- sulfenyl- ureido)-1-phenyl- cyclohexyl- methyl]- benzamide 522 66

trans-2- Methoxy-N- [4-(N-tert- butyl-N′- sulfenyl- ureido)-1- phenyl-cyclohexyl- methyl]- benzamide 474 67

trans-2- Methoxy-N- [4-(N- phenyl- N′- sulfenyl- ureido)-1- phenyl-cyclohexyl- methyl]- benzamide 494 68

trans-2- Methoxy-N- [4-(N,N- diethyl-N′- sulfenyl- ureido)-1- phenyl-cyclohexyl- methyl]- benzamide 474 69

trans-2- Methoxy-N- [4-(N- benzyl- N′- sulfenyl- ureido)-1- phenyl-cyclohexyl- methyl]- benzamide 508 70

trans-2- Methoxy-N- [4-(N- propyl- N′- sulfenyl- ureido)-1- phenyl-cyclohexyl- methyl]- benzamide 500 71

trans-2- Methoxy-N- [4-(N,N- dipropyl- N′-sulfenyl- ureido)- 1-phenyl-cyclohexyl- methyl]- benzamide 502 72

trans-2- Methoxy-N- [4-(N-(4-N- methyl- piperazinyl)- N′-sulfenyl-ureido)- 1-phenyl- cyclohexyl- methyl]- benzamide 501

EXAMPLE 73

cis-2-Methoxy-N-{4-[N-(4-anisoyl)-N′-sulfenylureido]-1-phenyl-cyclohexylmethyl}-benzamide

Synthesis:

Compound 1: The synthesis of 1 was described in Example 31.

Compound 2: Chlorosulfonyl isocyanate (0.22 ml, 2.5 mmol) was dissolvedin 2 ml of dichloromethane and cooled to 0° C. Chloroethanol (0.16 ml,0.25 mmol) was added slowly and the reaction mixture was stirred foradditional 1.5 h at 0° C. A solution of the cis-amine 1 (0.85 g, 2.5mmol) and Et₃N (0.8 ml, 7.6 mmol) in 30 ml of dichloromethane was addedslowly into the reaction mixture. The solution was allowed to warm to25° C. and stirred overnight. The reaction was quenched by dropwiseaddition of 2N HCl and saturated with NaCl. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane (60ml×3). The combined organic layer was dried over MgSO₄ and concentratedin vacuo, yielding a white solid, which was purified by columnchromatograophy (50% Hex/EtOAc) to provide 1.1 g (2.2 mmol, 87%) of 2 asa white solid.

Compound 3: A solution of 2 (17 mg, 0.035 mmol), and p-anisidine (10 mg,0.08 mmol) in 1 ml of CH₃CN was stirred for 2 h at 65° C. The reactionmixture was purified by preparative HPLC (described in a synthesis ofExample 31) to yield 3.2 mg of the 3 as a colorless oil. Mass Spec[M+H]⁺ 524.

EXAMPLES 74-147

Examples 74 to 147 were synthesized using methodology described inExample 73. Ex. Structure Name (M + H) 74

cis-2-Methoxy-N-[4-(N- methyl-N-benzyl-N′- sulfenylureido)-1-phenyl-cyclohexyl- methyl]-benzamide 522 75

cis-2-Methoxy-N-[4-(N- tert-butyl-N′- sulfenylurido)-1-phenyl-cyclohexyl- methyl]-benzamide 474 76

cis-2-Methoxy-N-[4-(N- phenyl-N′- sulfenylurido)-1- phenyl-cyclohexyl-methyl]-benzamide 494 77

cis-2-Methoxy-N-[4- (N,N-diethyl-N′- sulfenylurido)-1-phenyl-cyclohexyl- methyl]-benzamide 474 78

cis-2-Methoxy-N-[4-(N- benzyl-N′- sulfenylurido)-1- phenyl-cyclohexyl-methyl]-benzamide 508 79

cis-2-Methoxy-N-[4-(N- ethyl-N′-sulfenylurido)- 1-phenyl-cyclohexyl-methyl]-benzamide 446 80

cis-2-Methoxy-N-[4- (N,N-dipropyl-N′- sulfenylurido)-1-phenyl-cyclohexyl- methyl]-benzamide 502 81

cis-2-Methoxy-N-[4-(N- propyl-N′- sulfenylurido)-1- phenyl-cyclohexyl-methyl]-benzamide 460 82

cis-2-Methoxy-N-[4-(2- oxo-oxazolidine-3- sulfonylamino)-1-phenyl-cyclohexyl- methyl]-benzamide 488 83

cis-2-Methoxy-N-[4-(N- methyl-N′- sulfenylurido)-1- phenyl-cyclohexyl-methyl[-benzamide 432 84

cis-N-[4-(4-Phenyl- piperidine-1- sulfonylamino)-1- phenyl-cyclohexyl-methyl]-2-methoxy- benzamide 563 85

cis-N-[4-(4-Cyano-4- phenyl-piperidine-1- sulfonylamino)-1-phenyl-cyclohexyl- methyl]-2-methoxy- benzamide 587 86

cis-N-[4-(4-Methyl- piperidine-1- sulfonylamino)-1- phenyl-cyclohexyl-methyl]-2-methoxy- benzamide 501 87

cis-2-Methoxy-N-[4-(N- Allyl-N′-sulfenylurido)- 1-phenyl-cyclohexyl-methyl]-benzamide 458 88

cis-2-Methoxy-N-{4-[N- (3-isoxazol)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 485 89

cis-2-Methoxy-N-{4-[N- (3-cyano-phenyl)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 519 90

cis-2-Methoxy-N-{4-[N- (4-methylbenzyl)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 522 91

cis-2-Methoxy-N-{4-[N- (5-methyl-1H-3- pyrazol)-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 498 92

cis-2-Methoxy-N-{4-[N- 1-(3-N,N-diethyl- propyl)-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl}]- benzamide 531 93

cis-2-Methoxy-N-{4-[N- 1-(3-N,N-dimethyl-2,2- dimethyl-propyl)-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl}]- benzamide 531 94

cis-2-Methoxy-N-[4-(N- methyl-N-2- hydroxyethyl-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl]- benzamide 476 95

2-Methoxy-N-[4- (morpholine-4- sulfonylamino)-1- phenyl-cyclohexyl-methyl]-benzamide 488 96

cis-N-[4-(4-Methyl- piperidine-1- sulfonylamino)-1- phenyl-cyclohexyl-methyl]-2-methoxy- benzamide 515 97

cis-2-Methoxy-N-{4-[N- (ethoxy2-ethyl)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 490 98

cis-2-Methoxy-N-[4-(N- indan-1-yl-N′- sulfenylurido)-1-phenyl-cyclohexyl-methyl]- benzamide 534 99

cis-2-Methoxy-N-{4-[N- (2,4-difluoro-benzyl)-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 544 100

cis-2-Methoxy-N-{4- [N,N-di(2-hydroxy- ethyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 506 101

cis-2-Methoxy-N-{4-[N- methyl-N-(pyridin-2-yl- ethyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 537 102

cis-2-Methoxy-N-{4-[N- (pyridin-2-yl-methyl)- N′-sulfenyl-urido]-1-phenyl-cyclohexyl- methyl}- benzamide 509 103

cis-2-Methoxy-N-{4-[N- (4-methyl-pyridin-2-yl)- N′-sulfenylurido]-1-phenyl-cyclohexyl- methyl}- benzamide 509 104

cis-2-Methoxy-N-{4-[N- (3-fluoro-phenyl)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 512 105

cis-2-Methoxy-N-{4-[N- (4-anisoyl)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 524 106

cis-2-Methoxy-N-{4-[N- (3-fluoro-4-methyl)- phenyl)-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 526 107

cis-2-Methoxy-N-{4-[N- (tetrazol-5-yl)-N′- sulfenyl-urido]-1-phenyl-cyclohexyl-methyl}- benzamide 486 108

cis-2-Methoxy-N-{4-[N- (1H-pyrazol-3-yl)-N′- sulfenyl-urido]-1-phenyl-cyclohexyl-methyl}- benzamide 484 109

cis-2-Methoxy-N-{4-[N- (4-fluoro-□-methyl- benzyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 540 110

N-[4-(4-Acetyl- [1,4]diazepane-1- sulfonylamino)-1- phenyl-cyclohexyl-methyl]-2-methoxy- benzamide 543 111

cis-2-Methoxy-N-[4-(N- methyl-N-propyl-N′- sulfenylurido)-1-phenyl-cyclohexyl-methyl]- benzamide 474 112

cis-2-Methoxy-N-{4-[N- (2-methoxyethyl)-N′- sulfenylurido]-1-phenyl-cyclohexyl-methyl}- benzamide 476 113

cis-2-Methoxy-N-{4-[N- (2,2,2-trifluoroethyl)-N′-sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 500 114

cis-2-Methoxy-N-{4-[N- (4-fluoro-benzyl)-N′- sulfenyl-urido]-1-phenyl-cyclohexyl-methyl}- benzamide 526 115

cis-2-Methoxy-N-{4-[N- (2-methyl-2-propen-1- yl)-N′-sulfenyl-urido]-1-phenyl-cyclohexyl- methyl}-benzamide 472 116

cis-2-Methoxy-N-{4-[N- (2-methyl-1-propan-1- yl)-N′-sulfenyl-urido]-1-phenyl-cyclohexyl- methyl}- benzamide 474 117

cis-2-Methoxy-N-{4-[N- (imidazol-4-ylethyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 512 118

N-{4-[4-(4-Fluoro- phenyl)-piperazine-1- sulfonylamino]-1-phenyl-cyclohexyl- methyl}-2-methoxy- benzamide 581 119

2-Methoxy-N-[1-phenyl- 4-(piperazine-1- sulfonylamino)-cyclohexylmethyl]- benzamide 457 120

cis-2-Methoxy-N-{4-[N- methyl-N-1-(2-N,N- dimethyl-ethyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 503 121

cis-2-Methoxy-N-[4-(N- cyclohexyl-methyl-N′- sulfenyl-urido)-1-phenyl-cyclohexyl-methyl]- benzamide 514 122

cis-2-Methoxy-N-{4-[N- (pyridin-2-yl)-N′- sulfenyl-urido]-1-phenyl-cyclohexyl-methyl}- benzamide 495 123

cis-2-Methoxy-N-{4-[N- 1-(2-hydroxymethyl- propyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 490 124

cis-2-Methoxy-N-{4-[N- (bis-hydroxymethyl- methyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 492 125

cis-2-Methoxy-N-{4-[N- 1-(2-hydroxymethyl-3- methyl-propyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 504 126

cis-2-Methoxy-N-{4-[N- 1-(1-hydroxymethyl- ethyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 476 127

N-[4-((R)3-Hydroxy- pyrrolidine-1- sulfonylamino)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 488 128

cis-2-Methoxy-N-{4-[N- 1-(2-hydroxy-propyl)- N′-sulfenyl-urido]-1-phenyl-cyclohexyl- methyl}- benzamide 476 129

N-[4-((S)3-Hydroxy- pyrrolidine-1- sulfonylamino)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 488 130

cis-2-Methoxy-N-{4-[N- methyl-N-1-(2-methoxy ethyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 490 131

cis-2-Methoxy-N-{4-[N- 1-((S)-2,3-dihydroxy- propyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 492 132

N-[4-(3-Hydroxy- piperidine-1- sulfonylamino)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 502 133

N-[4-((R)-2- Hydroxymethyl- pyrrolidine-1- sulfonylamino)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 502 134

N-[4-((s)-2- Hydroxymethyl- pyrrolidine-1- sulfonylamino)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 502 135

cis-2-Methoxy-N-{4-[N- ((R)-tetrahydrofuran-2- yl-methyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 502 136

cis-2-Methoxy-N-{4-[N- ((S)-tetrahydrofuran-2- yl-methyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 502 137

cis-2-Methoxy-N-{4-[N- 1-(1-methoxymethyl- propyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 504 138

cis-2-Methoxy-N-{4-[N- C-(3,4-dihydro-2H- pyran-2- yl)methylamino]-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 514 139

N-[4-(2,6-Dimethyl- morpholine-4- sulfonylamino)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 516 140

cis-2-Methoxy-N-[4-(N- α-(R)-hydroxymethyl- benzyl-N′-sulfenyl-urido)-1-phenyl- cyclohexyl-methyl]- benzamide 538 141

cis-2-Methoxy-N-[4-(N- α-(S)-hydroxymethyl- benzyl-N′-sulfenyl-urido)-1-phenyl- cyclohexyl-methyl]- benzamide 538 142

cis-2-Methoxy-N-{4-[N- 1-((R)-2,3-dihydroxy- propyl)-N′-sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 492 143

cis-2-Methoxy-{N-[4- (N,4-ethylacetylphenyl- N′-sulfenyl-urido]-1-phenyl-cyclohexyl- methyl}-benzamide 580 144

cis-2-Methoxy-{N-[4- (N-4-(2- hydroxyethyl)phenyl)-N′-sulfenyl-urido]-1- phenyl-cyclohexyl- methyl}-benzamide 538 145

cis-2-Methoxy-{N-[4- (N-4-(1- hydroxyethyl)phenyl)-N′-sulfenyl-urido]-1- phenyl-cyclohexyl- methyl}-benzamide 538 146

cis-2-Methoxy-{N-[4- (N-4- hydroxymethylphenyl)- N′-sulfenyl-urido-1-phenyl]-cyclohexyl- methyl}-benzamide 524 147

cis-2-Methoxy-{N-[4- (N-2-hydroxy-indan-1- yl)-N′-sulfenyl-urido-1-phenyl]-cyclohexyl- methyl}-benzamide 550

EXAMPLE 148

cis-N-[4-(N′-Ethyl-guanidino)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of compound 1 was described in Example 31.

Compound 2: To a solution of the amine 1 (0.35 g, 1.0 mmol) in 10 ml ofdichloromethane and 5 ml of aq. NaHCO₃ was added thiophosgene (0.3 ml,4.0 mmol) in one portion. The reaction mixture stirred for 2 h at 25° C.The organic layer was then separated and concentrated in vacuo toprovide an oil (0.34 g, 89%). The oil was dissolved in 10 ml of 7NNH₃/MeOH and stirred for 12 h at 25° C. The reaction mixture wasconcentrated in vacuo to provide 2 as an oil which was used in thefollowing reaction without further purification.

Compound 3: To a solution of 2 in 10 ml of CH₃CN was added Mel (0.5 ml)and the resulting solution was stirred for 12 h at 25° C. The reactionmixture was concentrated in vacuo to provide a white solid which waspartitioned between EtOAc (50 ml) and brine (20 ml). The organic layerwas dried over MgSO₄ and concentrated in vacuo to yield 350 mg (>95%) of3 as an oil which was subjected to the following reaction withoutfurther purification.

Compound 4: To a solution of 3 (0.17 g, 0.45 mmol) in 10 ml ofdichloromethane was added triethylamine (0.2 ml) and acetyl chloride(0.2 ml, 2.8 mmol) and the resulting solution was stirred for 1 h at 0°C. The reaction mixture was diluted with EtOAc (50 ml) and washed withbrine (10 ml×2). The organic layer was dried over MgSO₄ and concentratedin vacuo to yield 4 as a dark oil which was subjected to the followingreaction without further purification.

Compound 5: A solution of 4 (35 mg, 0.077 mmol) and ethylamine (1 mmol,0.5 ml of 2M NH₃ in THF) in 1 ml of 2-propanol was stirred for 12 h at70° C. in a sealed tube. The reaction mixture was then subjected toprearative HPLC purification (described in a synthesis of Example 31) toyield 17.9 mg (40%) of the desired product 5 as a colorless oil. MassSpec [M+H]⁺=409.

EXAMPLES 149-152

Examples 149 to 152 were synthesized using methodology described inExample 148. Ex. Structure Name (M + H) 149

cis-N-[4-(N′,N′- dimethyl-guanidino)-1- phenyl-cyclohexyl-methyl]-2-methoxy- benzamide 409 150

cis-N-[4-(N′-benzyl- guanidino)-1-phenyl- cyclohexyl-methyl]-2-methoxy-benzamide 471 151

cis-N-[4-(N′-methyl- guanidino)-1-phenyl- cyclohexyl-methyl]-2-methoxy-benzamide 395 152

cis-N-[4-(N′-allyl- guanidino)-1-phenyl- cyclohexyl-methyl]-2-methoxy-benzamide 421

EXAMPLE 153

cis-2,4-Dimethoxy-N-[4-(N-methyl-N′-cyanoguanidino)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1 The synthesis of 1 was described in Example 31.

Compound 2: To a solution of the amine 1 (1.0 g, 4.0 mmol) andtriethylamine (0.67 ml, 4.8 mmol) in 10 ml of dichloromethane was addedtrifluoroacetic anhydride (1.0 ml, 4.8 mmol) dropwise and the resultingsolution was stirred at −78° C. for 2 h. The reaction mixture wasconcentrated in vacuo to provide an oily residue which was partitionedbetween EtOAc (100 ml) and brine (20 ml×2). The organic layer was driedover MgSO₄ and concentrated in vacuo to provide the desired product 2(1.3 g, 0.38 mmol, >95%) as a colorless oil. It was subjected to thefollowing reaction without further purification.

Compound 3: The intermediate 2 (1.3 g) was dissolved in THF (50 ml).Into the solution was added 30 ml of 2N HCl and the resulting solutionwas stirred for 12 h at 25° C. The HPLC analysis showed the completedisappearance of the starting material and formation of a new product.The reaction mixture was diluted with EtOAc (100 ml) and washed with aq.NaHCO₃ (30 ml×2). The organic layer was dried over MgSO₄ andconcentrated in vacuo to provide 1.2 g (>95%) of 3 as an oil.

Compound 4: To the solution of the ketone 3 (1.2 g, 4 mmol) in MeOH (60ml) was added NH₄OAc (2.5 g, 31 mmol) followed by addition of NaBH(OAc)₃(1.4 g, 5.2 mmol) in one portion. The resulting solution was stirred for3 h at 25° C. The reaction mixture was concentrated and the resultingsolid was redissolved in EtOAc (100 ml) and washed with aq. NaOH (1M, 30ml×2). The organic layer was dried over MgSO₄ and concentrated in vacuoto provide an oil which is a 1:1 mixture of the cis and transdiastereomers of the desired amine 4.

Compound 5: To a solution of the amine 4 (0.30 g, 1 mmol) in 2-propanol(2 ml) was added diphenyl cyanocarbonidate (240 mg, 1 mmol) and theresulting solution was stirred for 3 h at 70° C. HPLC analysis indicatedcompletion of the reaction. The reaction mixture was cooled to 25° C.and transferred into a sealed tube. To the sealed tube was added 2 ml of2M MeNH₂ (4 mmol). The resulting solution was stirred for another 5 h at70° C. The reaction mixture was concentrated to 2 ml of solution andpurified on preparative HPLC (described in a synthesis of Example 31) toprovide cis-isomer (retention time: 2.90 min) (70 mg) and trans-isomer(retention time: 2.65 min) (60 mg) of compound 5.

Compound 6: The cis isomer of intermediate 5 (1.1 g, 2.9 mmol) wasdissolved in 40 ml of 1:1 mixture of MeOH-H₂O with 7% aq. K₂CO₃ and theresulting solution was stirred for 3 h at 25° C. HPLC analysis indicatedcompletion of the reaction. The reaction mixture was concentrated invacuo to provide a white solid, which was partitioned between EtOAc (100ml) and brine (20 ml×2). The aqueous layer was extracted with EtOAc (50ml). The organic layer was dried over MgSO₄ and concentrated in vacuo toprovide 0.81 g (>95%) of 6 as an oil which was subjected to thefollowing reaction without any further purification.

Compound 7: To a solution of the amine 6 (40 mg, 0.014 mmol) in 2 ml ofdichloromethane was added 2,4-dimethoxybenzoic acid (38 mg, 0.021 mmol),EDCI (60 mg, 0.031 mmol) and diisopropylethylamine (57 pL, 0.031 mmol)sequentially. The mixture as allowed to stirred for 30 h at 35° C. Thereaction mixture was purified on preparative HPLC (described in asynthesis of Example 31) to provide 6.7 mg of the desired product 7 as acolorless oil. Mass Spec [M+H]⁺=450.

EXAMPLES 154-170

Examples 154 to 170 were synthesized using methodology described inExample 153. Ex. Structure Name (M + H) 154

cis-2,4-Dimethoxy- N-[4-(N-methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 450 155

cis-2,4,5- Trimethoxy-N-[4-(N- methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 480 156

cis-2,3-Dimethoxy- N-[4-(N-methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 450 157

cis-2-Phenoxy-N-[4- (N-methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 482 158

cis-(2,4-Dimethoxy- pyridin-3-yl)-N-[4- (N-methyl-N′- cyanoguanidino)-1-phenyl- cyclohexylmethyl]- benzamide 451 159

cis-(2-Phenoxy- pyridin-3-yl)-N-[4- (N-methyl-N′- cyanoguanidino)-1-phenyl- cyclohexylmethyl]- benzamide 483 160

cis-2,3-Diethoxy-N- [4-(N-methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 478 161

cis-2-Methoxy-4- thiomethoxy-N-[4- (N-methyl-N′- cyanoguanidino)-1-phenyl- cyclohexylmethyl]- benzamide 466 162

cis-2-Methoxy-3- methyl-N-[4-(N- methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 434 163

cis-2-Isopropoxy-N- [4-(N-methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 448 164

cis-2,6-Dimethoxy-3- chloro-N-[4-(N- methyl-N′- cyanoguanidino)-1-phenyl- cyclohexylmethyl]- benzamide 485 165

2-Methoxy- naphthalene-1- carboxylic acid [4- (N′-methyl-cyanoguanidino)-1- phenyl- cyclohexylmethyl]- amide 470 166

cis-2,3,4-Triethoxy- N-[4-(N-methyl-N′- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 480 167

cis-(2-Methoxy- pyridin-3-yl)-N-[4- (N-methyl-N′- cyanoguanidino)-1-phenyl- cyclohexylmethyl]- benzamide 421 168

N-[4-(N′-Methyl- cyanoguanidino)-1- phenyl- cyclohexylmethyl]-2-trifluoromethoxy- benzamide 474 169

2-Ethoxy- naphthalene-1- carboxylic acid [4- (N′-methyl-cyanoguanidino)-1- phenyl- cyclohexylmethyl]- amide 484 170

2-Benzyloxy-N-[4- (N′-methyl- cyanoguanidino)-1- phenyl-cyclohexylmethyl]- benzamide 496

EXAMPLE 171

2-Methoxy-N-[4-(N-ethyl-N′-ethoxycarbonyl-guanidino)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1: The synthesis of 1 was described in Example 31.

Compound 2: To a solution of the amine 1 (mixture of cis and transisomers, 0.34 g, 1.0 mmol) in 15 ml of dichloromethane was added 0.12 mlof ethyl isothiocyanatoformate (0.12 ml, 1.0 mmol) at 0° C. The mixturewas stirred for 0.5 h at 0° C. and 3 h at 25° C. The reaction mixturewas diluted with 100 ml of dichloromethane and washed with IN HCl (20ml) and brine (20 ml). The organic solution was dried over MgSO₄ andconcentrated in vacuo to provide 0.43 g (95%) of the desired product 2as a colorless oil which was subjected to the following reaction withoutfurther purification.

Compound 3: To a solution of the intermediate 2 (50 mg, 0.11 mmol) in 5ml of dichloromethane was added ethylamine (0.1 ml of 2N in THF, 0.2mmol), EDCI (42 mg, 0.22 mmol) and diisopropylethylamine (0.02 ml, 0.11mmol) sequentially. The reaction mixture was stirred for 12 h at 25° C.The reaction mixture was purified by preparative HPLC (described in asynthesis of Example 31) to yield 22.2 mg (42%) of the desired product 3(1:1 mixture of cis- and trans-isomers) as a colorless oil. Mass Spec[M+H]⁺=481.

EXAMPLES 172-178

Examples 172 to 178 were synthesized using methodology described inExample 171. Ex. Structure Name (M + H) 172

2-Methoxy-N-[4-(N- ethyl-N′- ethoxycarbonyl- guanidino)-1-phenyl-cyclohexylmethyl]- benzamide 495 173

2-Methoxy-N-[4-(N- tert-butyl-N′- ethoxycarbonyl- guanidino)-1-phenyl-cyclohexylmethyl]- benzamide 509 174

2-Methoxy-N-[4-(N-n- hexyl-N′- ethoxycarbonyl- guanidino)-1-phenyl-cyclohexylmethyl]- benzamide 537 175

2-Methoxy-N-[4-(N,N- dipropyl-N′- ethoxycarbonyl- guanidino)-1-phenyl-cyclohexylmethyl]- benzamide 537 176

2-Methoxy-N-[4-(N- benzyl-N′- ethoxycarbonyl- guanidino)-1-phenyl-cyclohexylmethyl]- benzamide 543 177

2-Methoxy-N-[4-(N- methyl-N-benzyl-N′- ethoxycarbonyl-guanidino)-1-phenyl- cyclohexylmethyl]- benzamide 557 178

2-Methoxy-N-[4-(N- ethoxycarbonyl- guanidino)-1-phenyl-cyclohexylmethyl]- benzamide 453

EXAMPLE 179

cis-N-[4-(2,5-Dioxo-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of compound 1 was described in Example 31.

Compound 2: To a solution of the cis-amine (50 mg, 0.15 mmol) in 5 ml ofdichloromethane was added ethyl isocyanatoacetate (30 mg, 0.16 mmol) inone portion and the reaction mixture was stirred for 5 h at 25° C. Thereaction mixture was then concentrated in vacuo yielding an oilyresidue, which was dissolved in 1 ml of EtOH—3N aq.HCl (1:1 mixture).The mixture was stirred for 12 h at 45° C. The reaction mixture waspurified on preparative HPLC to yield 23.4 mg (37%) of the desiredproduct 2 as a white solid. Mass Spec [M+H]⁺=422.

EXAMPLE 180

cis-N-[4-(2,5-Dioxo-4-(s)-isopropyl-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1; The synthesis of 1 was described in Example 31.

Compound 2: The reaction was carried out in a same procedure asdescribed in Example 179 starting with the cis-amine 1 (50 mg, 0.15mmol) and methyl (S)-(−)-2-isocyanato-3-methylbutyrate (35 mg, 0.23mmol) to provide 16.7 mg (0.036 mmol, 24%) of the desired product as awhite solid. Mass Spec [M+H]⁺=464.

EXAMPLE 181

trans-N-[4-(2,5-Dioxo-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of 1 was described in Example 31.

Compound 2: The reaction was carried out in a same procedure asdescribed in Example 179 starting with the trans-amine (50 mg, 0.15mmol) ethyl isocyanatoacetate (30 mg, 0.16 mmol) to provide 6.4 mg(0.015 mmol, 10%) of the desired product as a white solid. Mass Spec[M+H]⁺=422.

EXAMPLE 182

trans-N-[4-(2,5-Dioxo-4-(s)-isopropyl-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of 1 was described in Example 31.

Compound 2: The reaction was carried out in a same procedure asdescribed in Example 180 starting with the trans-amine (50 mg, 0.15mmol) and methyl (S)-(−)-2-isocyanato-3-methylbutyrate (35 mg, 0.23mmol) to provide 23.4 mg (0.051 mmol, 33%) of the desired product as awhite solid. Mass Spec [M+H]⁺=464.

EXAMPLE 183

cis-N-[4-(2,5-Dioxo-4-(s)-tetrahydro-pyrrolo[1,2-C]imidazol-2-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide.

Synthesis:

Compound 1: The synthesis of 1 was described in Example 31.

Compound 2: To a solution of the cis-amine 1 (200 mg, 0.59 mmol) in 10ml of dichloromethane was added 10 ml of aq. NaHCO₃. To theheterogeneous solution was added 1 ml of phosgene (20% in toluene)dropwise and the resulting mixture was stirred for 5 h at 25° C. Theorganic layer was separated. The aqueous layer was extracted withdichloromethane (20 ml). The combined organic layer was dried over MgSO₄and concentrated in vacuo to provide an oil, which was identified as thedesired product 2 and subjected to the following reaction withoutfurther purification.

Compound 3: To a solution of the isocyanate 2 ( 1/10 of 2 produced inthe previous step) in 1 ml of 2-propanol was added 0.1 ml oftriethylamine and L-proline methyl ester.HCl (100 mg, 0.61 mmol) and theresulting solution was stirred for 12 h at 25° C. The reaction mixturewas mixed with 1 ml of 3N aq. HCl and the resulting solution was stirredfor 12 h at 70° C. It was cooled to 25° C. and purified by preparativeHPLC (described in a synthesis of Example 31) to provide 14.6 mg (53%)of the desired product 3 as a colorless oil. Mass Spec [M+H]⁺=462.

EXAMPLES 184-192

Examples 184 to 192 were synthesized using methodology described inExample 183. Ex. Structure Name (M + H) 184

cis-N-[4-(2,5-Dioxo-4- (s)-benzyl-imidazolin-1- yl)-1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 512 185

cis-N-[4-(2,5-Dioxo-4- (s)-isobutyl-imidazolin-1- yl)-1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 478 186

cis-N-[4-(2,5-Dioxo-4- (s)-ethyl-imidazolin-1- yl)-1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 450 187

cis-N-[4-(2,5-Dioxo-4- (s)-hydroxymethyl- imidazolin-1-yl)-1- phenyl-cyclohexylmethyl]-2- methoxy-benzamide 451 188

cis-N-{4-[2,5-Dioxo-4- (s)-(imidazo-4- yl)methyl-imidazolin-1-yl]-1-phenyl- cyclohexylmethyl}-2- methoxy-benzamide 502 189

cis-N-[4-(5,7-Dioxo- 4,6-diaza-spiro- [2.4]hept-6-yl)--1-phenyl-cyclohexyl- methyl]-2-methoxy- benzamide 448 190

cis-N-[4-(1,3-Dioxo-4- (s)-tetrahydro- imidazo[1,5-a]-pyridin-2-yl)-1-phenyl- cyclohexylmethyl]-2- methoxy-benzamide  76 191

cis-N-[4-(3-Benzyl-2,5- dioxo-imidazolidin-1- yl)-1-phenyl-cyclohexyl-methyl]-2- methoxy-benzamide 512 192

cis-N-[4-(3-Methyl-2,5- dioxo-imidazolidin-1- yl)-1-phenyl-cyclohexyl-methyl]-2- methoxy-benzamide 436

EXAMPLE 193

cis- andtrans-N-(2,4-Dioxo-1-phenyl-1,3-diaza-spiro[4,5]dec-8-ylmethyl)-2-methoxy-benzamide

Synthesis

Compound 1 The synthesis of 1 was described in Example 31.

Compounds 2 and 3: To a solution of the ketone (0.48 g, 1.42 mmol) in 20ml of 50% aq. EtOH was added KCN (0.11 g, 1.70 mmol) and (NH4)₂CO₃ (0.68g, 7.10 mmol) in one portion, respectively and the resulting solutionwas stirred for 12 h at 55° C. The mixture was concentrated in vacuoyielding an aqueous solution, which was extracted with EtOAc (100 ml×3).The organic layer was dried over MgSO₄ and concentrated in vacuoyielding a colorless oil. Upon dissolving the oil in dichloromethane awhite solid precipitated out. The white solid (230 mg) was comprised oftwo diastereoisomers in a 1:1 ratio. The mother liquor was concentratedin vacuo to provide an oil, which was purified on prep-HPLC (describedin a synthesis of Example 31) to yield 16.1 mg of one isomer (retentiontime: 2.82 min). The white solid was dissolved in 30 ml of hot EtOH andstored for 5 days at 25° C. to provide 55.7 mg a white solid precipitateof the other isomer. Mass Spec for both compounds [M+H]⁺=408.

EXAMPLE 194

cis-2-Methoxy-N-[4-(2-oxo-imidazolidin-1-yl)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1: The synthesis of compound 1 was described in Example 31.

Compounds 2 and 3: To a solution of the ketone 1 (0.5 g, 1.5 mmol) in 10ml of dichloroethane was added N-acetylethylenediamine (0.34 ml, 3.0mmol) and NaBH(OAc)₃ (0.64 g, 3.0 mmol) in a portion, respectively andthe resulting solution was stirred for 12 h at 25° C. It was dilutedwith dichloromethane (50 ml) and washed with 1N aq. NaOH. Organic layerwas separated and concentrated in vacuo to provide oily residue. Theresidue was dissolved in 20 ml of dichloromethane and stirred with 1.0 g(4.5 mmol) of di-tert-butyl dicarbonate for 1 h at 25° C. The reactionmixture was concentrated in vacuo yielding an oily residue which waspurified on preparative HPLC (described in the synthesis of Example 31)to provide both cis-2 (retention time: 2.42 min) and trans-3 (retentiontime: 2.57 min) isomers.

Compound 4: Compound 2 was dissolved in 20 ml of 3N aq. HCl and stirredfor 12 h at 25° C. The reaction was cooled to 0° C., basified with 20%aq. NaOH and extracted with dichloromethane (50 ml×3). The organic layerwas dried over MgSO₄ and concentrated in vacuo to provide 157 mg of 4.

Compound 5: The cis-amine 4 (100 mg, 0.26 mmol) was dissolved in 5 ml ofdichloromethane and stirred with carbonyldiimdazole (100 mg, 0.61 mmol)for 12 h at 25° C. The reaction mixture was concentrated and subjectedto preparative HPLC (described in the synthesis of Example 31) to yield14.6 mg of the desired product as a white solid. Mass Spec [M+H]⁺=408.

EXAMPLE 195

trans-2-Methoxy-N-[4-(2-oxo-imidazolidin-1-yl)-1-phenyl-cyclohexylmethyl]-benzamide

Synthesis:

Compound 1: The synthesis of compound 1 was described in Example 31.

Compounds 2 and 3: The synthesis of compounds 2 and 3 is described inExample 194.

Compound 4: Compound 3 was dissolved in 20 ml of 3N aq. HCl and stirredfor 12 h at 25° C. The reaction was cooled to 0° C., basified with 20%aq. NaOH and extracted with dichloromethane (50 ml×3). The organic layerwas dried over MgSO₄ and concentrated in vacuo to provide 135 mg of 4.

Compound 5: The trans-amine 4 (100 mg, 0.26 mmol) was dissolved in 5 mlof dichloromethane and stirred with carbonyldiimdazole (100 mg, 0.61mmol) for 12 h at 25° C. The reaction mixture was concentrated andsubjected to preparative HPLC (described in the synthesis of Example 31)to yield 15.8 mg of the desired product as a white solid. Mass Spec[M+H]⁺=408.

EXAMPLE 196

cis-N-[4-(2-Cyanoimino-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of 1 was described in Example 194.

Compound 2; A solution of the cis-amine (75 mg, 0.20 mmol) and diphenylcyanocarbonidate (75 mg, 0.32 mmol) in 3 ml of 2-propanol was stirredfor 4 h at 70° C. The reaction mixture was purified on preparative HPLC(described in Example 31) to provide 32.0 mg (37%) of the desiredproduct 2 as a colorless oil.

Mass Spec [M+H]⁺=432.

EXAMPLE 197

trans-N-[4-(2-Cyanoimino-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of 1 was described in Example 194.

Compound 2 The reaction was carried out in a same procedure described inExample 196, starting with 75 mg (0.20 mmol) of the trans-amine anddiphenyl cyanocarbonidate (75 mg, 0.32 mmol) to provide 47.6 mg (0.11mmol, 55%) of the desired product 2 as a white solid. Mass Spec[M+H]⁺=432.

EXAMPLE 198

1-Phenyl-cyclohexanecarboxylic acid benzylamide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2 A suspension of 1-phenyl-cyclohexanecarboxylic acid 1 (0.010g; 0.049 mmol) in methylene chloride (1 mL) was cooled to 0° C. andtreated with triethylamine (0.010 mL; 0.072 mmol) followed bytetramethylfluoroformamidinium hexafluorophosphate (0.014 g; 0.053mmol). After warming to room temperature (approximately 1 h), thesolvent was removed and the residue was used in the subsequent reaction.

Compound 3: Compound 2 was dissolved in acetonitrile (1 mL). PS-DIEA(polystrene-diisopropylethylamine resin; 0.2 g) was added and theresulting suspension was treated with benzyl amine (0.006 mg; 0.056mmol) and shaken at room temperature. After 12 h, PS-TsCl(polystrene-tosyl chloride, high loading resin; 0.2 g) was added and thereaction mixture is allowed to shake an additional 12 h. The reactionmixture was filtered and concentrated to give 0.011 g (79%) of compound3.

LCMS m/z=294.4 (M+H)⁺

EXAMPLES 199-289

Examples 199 to 289 were synthesized using methodology described inExample 198. In some cases, further purification was accomplished usingreverse phase HPLC. Ex. Structure Name M + H 199

1-Phenyl- cyclohexanecarboxylic acid 3,4-difluoro- benzylamide 330.4 200

1-Phenyl- cyclohexanecarboxylic acid 4-chloro- benzylamide 328.9 201

1-Phenyl- cyclohexanecarboxylic acid [2-(4-methoxy- phenyl)-ethyl]-amide338.5 202

1-Phenyl- cyclohexanecarboxylic acid 2,4-dimethoxy- benzylamide 354.5203

1-Phenyl- cyclohexanecarboxylic acid (1-phenyl-ethyl)- amide 308.4 204

1-Phenyl- cyclohexanecarboxylic acid 3-phenyl- propyl)-amide 322.5 205

1-Phenyl- cyclohexanecarboxylic acid 2-methoxy- benzylamide 324.4 206

1-Phenyl- cyclohexanecarboxylic acid 2-chloro- benzylamide 328.9 207

(1-Phenyl- cyclohexyl)- (4-phenyl-piperazin-1- yl)-methanone 349.5 208

1-Phenyl- cyclohexanecarboxylic acid (biphenyl-3- ylmethyl)-amide 370.5209

1-Phenyl- cyclohexanecarboxylic acid 3-fluoro-5- trifluoromethyl-benzylamide 380.4 210

1-Phenyl- cyclohexanecarboxylic acid (1-phenyl- ethyl)-amide 308.4 211

1-Phenyl- cyclohexanecarboxylic acid (1-phenyl- ethyl)-amide 308.4 212

1-Phenyl- cyclohexanecarboxylic acid (3,3-diphenyl- propyl)-amide 398.6213

1-Phenyl- cyclohexanecarboxylic acid 4- trifluoromethyl- benzylamide362.4 214

(4-Benzo[1,3]dioxol- 5-ylmethyl- piperazin-1-yl)-(1- phenyl-cyclohexyl)-methanone 407.5 215

1-Phenyl- cyclohexanecarboxylic acid 3-methyl- benzylamide 308.4 216

1-Phenyl- cyclohexanecarboxylic acid 3,4-dichloro- benzylamide 363.3 217

1-Phenyl- cyclohexanecarboxylic acid 4-methyl- benzylamide 308.4 218

1-Phenyl- cyclohexanecarboxylic acid (biphenyl-2- ylmethyl)-amide 370.5219

1-Phenyl- cyclohexanecarboxylic acid (4-phenyl- butyl)-amide 336.5 220

1-Phenyl- cyclohexanecarboxylic acid [2-(4-chloro- phenyl)-ethyl]-amide342.9 221

1-Phenyl- cyclohexanecarboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]- amide 376.4 222

1-Phenyl- cyclohexanecarboxylic acid [2-(2-fluoro- phenyl)-ethyl]-amide326.4 223

1-Phenyl- cyclohexanecarboxylic acid 3- trifluoromethyl- benzylamide362.4 224

1-Phenyl- cyclohexanecarboxylic acid 4-fluoro- benzylamide 312.4 225

1-Phenyl- cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide 324.4 226

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid (4-phenyl- butyl)-amide370.9 227

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 377.3 228

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]-amide 410.9 229

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 360.9 230

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid 4-chloro- benzylamide363.3 231

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid 3- trifluoromethyl-benzylamide 396.9 232

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid 4-fluoro- benzylamide346.8 233

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid (biphenyl-2-ylmethyl)-amide 405.0 234

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid 4- trifluoromethyl-benzylamide 396.9 235

1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide358.9 236

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid (4-phenyl- butyl)-amide354.5 237

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 360.9 238

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]-amide 394.4 239

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 344.4 240

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-chloro- benzylamide346.8 241

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid 3- trifluoromethyl-benzylamide 380.4 242

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid 4- fluoro- benzylamide330.4 243

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid (biphenyl-2-ylmethyl)-amide 387.5 244

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid 4- trifluoromethyl-benzylamide 380.4 245

1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide342.4 246

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid (4-phenyl- butyl)-amide354.5 247

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 360.9 248

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]-amide 394.4 249

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 344.4 250

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-chloro- benzylamide346.8 251

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid 3- trifluoromethyl-benzylamide 380.4 252

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-fluoro-benzylamide330.4 253

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid (biphenyl-2-ylmethyl)-amide 388.5 254

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid 4- trifluoromethyl-benzylamide 380.4 255

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid (2-phenoxy-ethyl)- amide341.4 256

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid (4-phenyl- butyl)-amide354.5 257

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 360.9 258

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(3- trifluoromethyl-phenyl)-ethyl]-amide 384.4 259

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 344.4 260

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-chloro- benzylamide346.8 261

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid 3- trifluoromethyl-benzylamide 380.4 262

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-fluoro- benzylamide330.4 263

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid (biphenyl-2-ylmethyl)-amide 387.5 264

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid 4- trifluoromethyl-benzylamide 380.4 265

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide342.4 266

1-p-Tolyl- cyclohexanecarboxylic acid [2-(3,4- dimethyl-phenyl)- ethyl]-amide 350.5 267

1-p-Tolyl- cyclohexanecarboxylic acid (2-m-tolyl- ethyl)-amide 336.5 268

1-p-Tolyl- cyclohexanecarboxylic acid [2-(4-bromo- phenyl)-ethyl]-amide401.4 269

1-p-Tolyl- cyclohexanecarboxylic acid (2-p-tolyl- ethyl)-amide 336.5 270

1-p-Tolyl- cyclohexanecarboxylic acid (3-phenyl- propyl)-amide 336.5 271

1-p-Tolyl- cyclohexanecarboxylic acid [2-(2-chloro- phenyl)-ethyl]-amide356.9 272

1-p-Tolyl- cyclohexanecarboxylic acid [2-(4-chloro- phenyl)-ethyl]-amide356.9 273

1-p-Tolyl- cyclohexanecarboxylic acid [2-(2,4- dichloro-phenyl)-ethyl]-amide 391.4 274

1-p-Tolyl- cyclohexanecarboxylic acid [2-(3-chloro- phenyl)-ethyl]-amide356.9 275

1-p-Tolyl- cyclohexanecarboxylic acid 4-fluoro- benzylamide 326.4 276

1-p-Tolyl- cyclohexanecarboxylic acid [2-(3,4- dichloro-phenyl)-ethyl]-amide 391.4 277

1-p-Tolyl- cyclohexanecarboxylic acid 3-methyl- benzylamide 322.5 278

1-p-Tolyl- cyclohexanecarboxylic acid (4-phenyl- butyl)-amide 350.5 279

1-p-Tolyl- cyclohexanecarboxylic acid [2-(2-methoxy-phenyl)-ethyl]-amide 352.5 280

1-p-Tolyl- cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide 338.5 281

1-p-Tolyl- cyclohexanecarboxylic acid (biphenyl-2- ylmethyl)-amide 384.5282

1-p-Tolyl- cyclohexanecarboxylic acid (2-thiophen-2- yl-ethyl)-amide328.5 283

1-p-Tolyl- cyclohexanecarboxylic acid 4-methoxy- benzylamide 338.5 284

1-p-Tolyl- cyclohexanecarboxylic acid [2-(4-ethyl- phenyl)-ethyl]-amide350.5 285

1-p-Tolyl- cyclohexanecarboxylic acid [2-(2-fluoro- phenyl)-ethyl]-amide340.5 286

1-p-Tolyl- cyclohexanecarboxylic acid 4-methyl- benzylamide 322.5 287

1-p-Tolyl- cyclohexanecarboxylic acid 3-methoxy- benzylamide 338.5 288

1-p-Tolyl- cyclohexanecarboxylic acid 2-methoxy- benzylamide 338.5 289

1-p-Tolyl- cyclohexanecarboxylic acid (1-phenyl- ethyl)-amide 322.5

EXAMPLE 290

1-(4-fluoro-phenyl)-cyclohexanecarboxylic acid[2-(4-chloro-phenyl)-ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: A suspension 2-(4-chlorophenyl)ethylamine (2.25 mL; 16.1mmol) and sodium sulfate (10.0 g; 70.4 mmol) in methanol (20 mL) wastreated with 1-methyl-1H-imidazole-2-carbaldehyde (1.80 g; 16.3 mmol)and heated to 40° C. After 24 h, the reaction mixture was cooled to 0°C., treated with sodium borohydride (0.73 g; 19.3 mmol) and allowed toslowly warm to room temperature. After 3 h, the solvent was removed andthe crude residue was partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The organic layer was separated, washed withsaturated aqueous sodium chloride, dried (magnesium sulfate) andconcentrated. The oily residue was dissolved in tetrahydrofuran andtreated with a solution of 1N HCl in diethyl ether (35 mL). A whiteprecipitate formed immediately and was collected to give 5 g (96%) of[2-(4-chloro-phenyl)-ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amine.2HCl.LCMS m/z=250.7 (M+H)⁺

Compound 3: A suspension of 1-(4-fluoro-phenyl)-cyclohexanecarboxylicacid (0.106 mg; 0.48 mmol) in methylene chloride (10 mL) was treatedwith oxalyl chloride (0.042 mL; 0.48 mmol) and 1 drop ofN,N-dimethylformamide. The reaction mixture was allowed to stir at roomtemperature for 15 min at which time triethylamine (0.28 mL; 2.0 mmol)and[2-(4-Chloro-phenyl)-ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amine.2HCl(0.16 g; 0.50 mmol) was added. After an addition 30 min of stirring thesolvent was removed and the residue was purified using reverse phaseHPLC to give 0.114 g (52%) of 3 as a white solid. LCMS m/z=455.0 (M+H)⁺.

EXAMPLE 291

1-(4-Chloro-phenyl)-cyclohexanecarboxylicacid[2-(4-chloro-phenyl)ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amide

Synthesis:

The titled compound was prepared using methodology described in Example290. LCMS m/z=471.5 (M+H)⁺.

EXAMPLE 292

1-(4-fluoro-phenyl)-cyclohexanecarboxylic acidbenzyl-(1-methyl-1H-imidazol-2-ylmethyl)-amide

The titled compound was prepared using methodology described in Example290. LCMS m/z=406.5 (M+H)⁺

Example 293

Ethyl-carbamic acid4-[5-(3-methoxy-benzyl)-[1,2,4]oxadiazol-3-yl]-4-phenyl-cyclohexyl ester

Synthesis:

Compound 1: the synthesis of Compound 1 is described in Example 31.

Compound 2: A solution of compound 1 (5.8 g; 23.8 mmol), hydroxylaminehydrochloride (4.21 g; 60.6 mmol) and sodium methoxide (3.27 g; 60.6mmol) in n-propanol (100 mL) was heated at 98° C. overnight. Thereaction mixture was concentrated under reduced pressure, diluted withEtOAc (100 mL), washed with H₂O and dried over anhydrous sodium sulfate.Purification by flash chromatography (1:1; Hexanes:ethyl acetate) gave 2(4.6 g; 71%) as a white solid.

LCMS m/z=277.1 (M+H)⁺

Compound 3: To a solution of Compound 2 (0.100 g, 0.36 mmol) in2-methoxyethyl ether (5 mL) was added potassium carbonate (0.72 mmol)followed by 3-methoxyphenyl acetyl chloride (0.067 g, 0.36 mmol). Thereaction mixture was stirred at room temperature for 30 min. then heatedat 120° C. for 3 h. After cooling to room temperature, the reactionmixture was diluted with water, extracted with ethyl acetate and driedover anhydrous sodium sulfate. Purification by column chromatography onsilica gel (7:3 hexanes:ethyl acetate) gave 3 (0.085 g; 58%) as an oil.¹H NMR (CDCl₃, 300 MHz): δ(ppm) 1.65-1.80 (4 H, m), 2.25-2.40 (2 H, m),2.60-2.70 (2 H, m), 3.74 (3 H, s), 3.94 (4 H, s), 4.14 (2 H, s),6.75-6.90 (3 H, m), 7.15-7.45 (6 H, m); LCMS m/z=407.2 (M+H)⁺.

Compound 4: A solution of Compound 3 (80 mg, 0.20 mmol) intetrahydrofuran (1.25 mL) was treated with 2 N HCl (0.4 mL) and heatedat 40° C. for 6 h. Saturated aqueous sodium bicarbonate was added. Theaqueous phase was extracted with ethyl acetate and the organic phasedried over anhydrous sodium sulfate. Purification by columnchromatography on silica gel (7:3 hexanes:ethyl acetate) gave 4 (40 mg;60%) as an oil. LCMS m/z=363.2 (M+H)⁺.

Compound 5: A solution of 4 (1.2 g, 3.31 mmol) in tetrahydrofuran (20mL) at 0° C. was treated with sodium borohydride (250 mg, 6.62 mmol).After stirring from 0° C. to room temperature overnight, the reactionmixture was quenched with saturated aqueous sodium carbonate andextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. Purification by column chromatography on silica gel (7:3hexanes:ethyl acetate) gave 5 (1.12 g, 93%). LCMS m/z=365.5 (M+H)⁺.

Compound 6: ¹H NMR (CDCl₃, 300 MHz): δ(ppm) 1.11 (3 H, t, J=7.1 Hz),1.50-1.70 (2 H, m), 1.90-2.18 (4 H, bd, J=9.7 Hz), 2.88 (2 H, bd, J=13.6Hz), 3.10-3.25 (2 H, m), 3.74 (3 H, s), 4.14 (2 H, s), 4.60-4.80 (2 H,m), 6.70-6.90 (3 H, m), 7.08-7.40 (6 H, m). LCMS m/z=436.2 (M+H)⁺.

EXAMPLES 294-322

Examples 294 to 322 were synthesized using methodology described inExample 293. In some cases, further purification was accomplished usingreverse phase HPLC. Ex. Structure Name M + H 295

4-Phenyl-4-(5- phenyl- [1,2,4]oxadiazol-3- yl)-cyclohexanone 319.4 296

4-[5-(2-Methoxy- phenyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-cyclohexanone 349.4 297

Ethyl-carbamic acid 4-phenyl-4-(5- phenyl- [1,2,4]oxadiazol-3-yl)-cyclohexyl ester 392.5 298

Ethyl-carbamic acid 4-[5-(2-methoxy- phenyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 422.5 299

Ethyl-carbamic acid 4-[5-(3-chloro- phenyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 426.9 300

Ethyl-carbamic acid 4-[5-(4-chloro- phenyl- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 426.9 301

Ethyl-carbamic acid 4-phenyl-4-(5-p- tolyl- [1,2,4]oxadiazol-3-yl)-cyclohexyl ester 406.5 302

[2-(1-Methyl- pyrrolidin-2-yl)- ethyl]-carbamic acid 4-[5-(3-methoxy-benzyl)- [1,2,4]-oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 519.7 303

Thiophen-2- ylmethyl-carbamic acid 4-[5-(3- methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 504.6 304

4-Phenyl-butyl)- carbamic acid 4-[5- (3-methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 540.7 305

Cyclopropylmethyl- carbamic acid 4-[5- (3-methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 462.6 306

(2-Pyridin-4-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 513.6 307

(Tetrahydro-furan-2- ylmethyl)-carbamic acid 4-[5-(3- methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 492.6 308

2-Thiophen-2-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 518.6 309

(2-Pyridin-2-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 513.6 310

Isobutyl-carbamic acid 4-[5-(3- methoxy-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 464.6 311

Phenethyl-carbamic acid 4-[5-(3- methoxy-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 512.6 312

Butyl-carbamic acid 4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 464.6 313

Allyl-carbamic acid 4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 448.5 314

Cyclohexyl-carbamic acid 4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 490.6 315

Pyridin-4-ylmethyl- carbamic acid 4-[5- (3-methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 499.6 316

Propyl-carbamic acid 4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 450.5 317

Cyclopentyl- carbamic acid 4-[5- (3-methoxy-benzyl)- [1,2,4]oxadiazol-3-yl]-4-phenyl- cyclohexyl ester 476.6 318

(2-Methoxy-ethyl)- methyl-carbamic acid 4-[5-(3-methoxy- benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 480.6 319

Cyclohexylmethyl- carbamic acid 4-[5- (3-methoxy- benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl cyclohexyl ester 504.6 320

(2-Pyridin-3-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl cyclohexyl ester 513.6 321

(2,4-Dichloro- benzyl)-carbamic acid 4-[5-(3- methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 567.5 322

Benzyl-methyl- carbamic acid 4-[5- (3-methoxy-benzyl)-[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 512.6

EXAMPLE 323

Ethyl-carbamic acid 4-(isoquinolin-1-ylaminomethyl)-4-phenyl-cyclohexylester

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 31

Compound 2: is commercially available

Compound 3: A mixture of compound 1 (2.0 g, 8.09 mmol), 2 (1.1 g, 6.75mmol), sodium-t-butoxide (908 mg, 9.75 mmol), palladium acetate (75.7mg, 0.34 mmol) and 2-(di-t-butylphosphino)biphenyl (100.7 mg, 0.3374mmol) in toluene (20 mL) was heated at 110° C. for 20 h. The insolubleswere filtered off through CELITE, the solvent was removed under reducedpressure and the residue was purified by flash chromatography throughsilica eluting with 40% ethyl acetate-hexane providing the titlecompound (1.5 g, 50% yield) as a yellow oil.

Compound 4: Dioxolane 3 (1.5 g) was dissolved in THF, diluted with 2NHCl and stirred overnight. The solution was added to a mixture of ethylacetate and saturated sodium bicarbonate. The organic solution waswashed with an additional two portions of bicarbonate solution followedby brine. The solution was dried over sodium sulfate and the solventremoved under reduced pressure providing 1.25 g (94%) of Compound 4 asan orange syrup which was used without further purification.

Compounds 5 and 6: Sodium borohydride (215 mg, 5.82 mmol) was added to asolution of ketone 4 (1.25 g, 3.79 mmol) in THF (10 mL) and the mixturewas stirred overnight. The reaction was partitioned between ethylacetate and dilute HCl. The aqueous layer was basified with saturatedsodium bicarbonate. The product was extracted into ethyl acetate whichwas dried over sodium sulfate and the solvent removed under reducedpressure. Flash chromatography through silica with ethyl acetate aseluent provided 5 (isomer A, 469 mg) and 6 (isomer B, 170 mg).

Compound 7: Camphorsulphonic acid (160.1 mg, 0.689 mmol) was added to astirred solution of 5 (114 mg, 0.344 mmol) in dichloromethane (10 mL).After 5 min. ethyl isocyanate (32.7 μL, 0.414 mmol) was added andstirring continued for 2 h. The reaction was quenched with a methanolicsolution of ammonia, the solvent was removed under reduced pressure andthe residue was flash chromatographed through silica eluting with 60%ethyl acetate-hexane, then 5% methanol-dichloromethane affording 10.2 mgof the title compound, [M+H] 404.

EXAMPLE 324

Ethyl-carbamic acid 4-(isoquinolin-1-ylaminomethyl)-4-phenyl-cyclohexylester

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 323.

Compound 2: In a reaction similar to that described in example 323,Compound 1 (76.3 mg, 0.230 mmol), camphorsulfonic acid (106.8 mg, 0.460mmol) and ethyl isocyanate (21.8 μL, 0.276 mmol) in dichloromethane (10mL) produced 16.3 mg of Compound 2, [M+H] 403.

EXAMPLE 325

Isoquinolin-1-yl-(1-phenyl-cyclohexylmethyl)-amine

Synthesis:

Compound 1: Compound 1 is commercially available

Compound 2: A suspension of 1-phenyl-1-cyclohexane carboxylic acid(0.484 g; 2.37 mmol) in methylene chloride (30 ml) was treated withoxalyl chloride (0.23 mL; 2.64 mmol) and 1 drop ofN,N-dimethylformamide. The reaction mixture was allowed to stir at roomtemperature for 30 minutes at which time triethylamine (1 mL; 7.2 mmol)and 1-aminoisquinoline (0.36 g; 2.50 mmol). After an additional 15minutes of stirring the reaction mixture was washed with water andsaturated aqueous sodium chloride, dried (magnesium sulfate) andconcentrated. The crude residue was purified by column chromatography onsilicia gel using 3:1:1 hexane:ethyl acetate:dichloromethane as theeluent to give 0.605 g of 1-phenyl-cyclohexanecarboxylic acidisoquinolin-1-ylamide as a white foam. LCMS m/z=331.2 (M+H)⁺

Compound 3: A solution of 1-phenyl-cyclohexanecarboxylic acidisoquinolin-1-ylamide (0.117 g; 0.35 mmol) in tetrahydrofuran (10 mL)was cooled to 0° C. and treated with lithium aluminum hydride (0.040 g;1.05 mmol). The reaction mixture was allowed to slowly warm to roomtemperature. After 18 h at room temperature additional lithium aluminumhydride was added (0.04 g; 1.05 mmol) and the reaction mixture washeated at 40° C. for 2 h. The reaction mixture was cooled back to 0° C.and carefully quenched by the dropwise addition of water. Thetetrahydrofuran was removed by evaporation and the crude residue wasdiluted with ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was separated, washed with saturated aqueous sodiumchloride, dried (magnesium sulfate), filtered and concentrated. Columnchromatography on silicia gel using 7:3 hexane:ethyl acetate as theeluent gave 0.042 g ofisoquinolin-1-yl-(1-phenyl-cyclohexylmethyl)-amine as a light yellowoil. LCMS m/z=317.2 (M+H)⁺; ¹H NMR (CDCl₃, 300 MHz) δ(ppm) 7.96 (1H, d,J=6.0 Hz), 7.54-7.26 (9 H, m), 6.61 (1H, d, J=6.0 Hz), 4.80 (1 H, broadS), 3.76 (2 H, d, J=5.4 hz), 2.26-2.20 (2 H, m), 1.84-1.77 (2 H, m),1.66-1.61 (2 H, m), 1.55-1.43 (4 H, m); ¹³C NMR (CDCl₃, 75 MHz) 155.4,144.9, 141.4, 137.1, 129.5, 128.9 (two carbons), 127.1, 127.0 (twocarbons), 126.4, 125.8, 121.0, 118.1, 110.5, 52.2, 42.6, 34.3 (twocarbons), 26.6, 22.2 (two carbons).

EXAMPLES 326-329

Exampless 326 to 329 were synthesized using methodology described inExample 325. Example Structure Name M + H 326

1-Phenyl- cyclohexanecarboxylic acid [1,7]naphthyridin- 8-ylamide 332.2327

[1,7]Naphthyridin-8-yl- (1-phenyl- cyclohexylmethyl)- amine 318.2 328

1-Phenyl- cyclopropanecarboxylic acid isoquinolin-1- ylamide 289.1 329

Isoquinolin-1-yl-(1- phenyl- cyclopropylmethyl)- amine 275.2

EXAMPLE 330

(1-phenyl-cyclohexylmethyl)-quinazolin-4-yl-amine

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: A solution of 1-phenyl-cyclohexanecarbonitrile (11.0 g; 59mmol) in tetrahydrifuran (100 mL) was cooled to 0° C. and treated withlithium aluminum hydride (11 g, 289 mmol) in several portions over thecourse of 0.5 h. When the addition of lithium aluminum hydride wascomplete the cooling bath was removed and the reaction mixture wasallowed to stir at room temperature for 12 h. The reaction mixturewascooled back to 0° C. and carefully quenched by dropwise addition of 2 NNaOH (approximately 20 mL), diluted with ethyl ether, filtered through acelite plug and dried (magnesium sulfate).C-(1-Phenyl-cyclohexyl)-methylamine was obtained as a colorless oilwhich was used without further purification. LCMS m/z=190.2 (M+H)⁺

Compound 3: A solution of C-(1-phenyl-cyclohexyl)-methylamine (0.28 g;1.48 mmol) in tetrahydrofuran (10 mL) at room temperature was treatedwith triethylamine (0.3 mL; 2.2 mmol) and 2,4-dichloro-quinazoline (0.32g; 1.62 mmol). The reaction was stirred at room temperature 12 h atwhich time the solvent was removed by rotary evaporation. The cruderesidue was portioned between ethyl acetate and 10% aqueous HCl. Theorganic layer was separated, washed with saturated aqueous sodiumchloride, dried (magnesium sulfate), filtered and concentrated. Theproduct was recyrstallized from methylene chloride to give(2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine as a whitesolid. LCMS m/z=352.2 (M+H)⁺

Compound 4: A solution of(2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine (0.065 g;0.18 mmol) in anhydrous methanol (2 mL) was treated with 10% palladiumon carbon (200 mg) and placed under an atmosphere of hydrogen (45 psi).The reaction mixture was shaken at room temperature for 3 h. Thereaction mixture was filtered through celite and evaporated. The cruderesidue was purified by column chromatography on silicia gel using 9:1ethyl acetate:hexane as the eluent to give 0.052 g(1-phenyl-cyclohexylmethyl)-quinazolin-4-yl-amine as a white foam. LCMSm/z=318.2 (M+H)⁺

EXAMPLE 331

N²-ethyl-N⁴-(1-phenyl-cyclohexylmethyl)-quinazoline-2,4-diamine

Synthesis:

Compound 1: Compound 1 is prepared as described above.

Compound 2: (2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine(0.052 g; 0.15 mmol) was treated with 1 mL of a 2 M solution ofethylamine in tetrahydrofuran. The reaction vessel was tightly sealedand the reaction mixture was heated at 60° C. for 24 h. The volatilecomponents were removed under vacuum and the crude residue was purifieddirectly be preparative HPLC to give 0.020 g ofN²-ethyl-N⁴-(1-phenyl-cyclohexylmethyl)-quinazoline-2,4-diamine as awhite solid. LCMS m/z=361.2 (M+H)⁺

EXAMPLE 332

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: To a refluxing solution of 2-flourophenylacetonitrile (5 ml,41 mmol) in 100 ml of acetonitrile was added dropwise methyl acrylate(36 ml, 400 mmol) in 100 ml of acetonitrile for 3 h period. Theresulting solution was stirred for additional 6 h at reflux. Reactionmixture was concentrated in vacuo, yielding oily residue, which waspurified on column chromatography (40% EtOAc/Hexane)to produce compound2 (11.2 g, 89%) as a colorless oil.

Compound 3: To a solution of compound 2 in 200 ml of DCM was added NaH(2.5 g, 108 mmol) in a portion and the resulting solution was stirred atreflux for 12 h. Reaction mixture was cooled to −78° C. and quenched byadding ice. The mixture was diluted with EtOAc (150 ml) and organiclayer was filtered out. The concentration of organic layer provided anoil (8.8 g, 89%), which corresponds to the desired product in NMRanalysis and was subjected to the following reaction without furtherpurification.

Compound 4: Compound 3 was dissolved in 80 ml of DMSO and 4 ml of H₂O.The mixture was stirred at 140° C. for 15 h. The reaction mixture wascooled down, diluted with EtOAc (400 ml) and washed with 10% aqueousLiCl (30 ml×3). The aqueous layer was extracted with EtOAc (50 ml×2).The combined organic layer was dried over MgSO₄ and concentrated invacuo to provide oily residue, which was purified on columnchromatography (25-50% EtOAc/hexane) to provide the desired product (5.5g, 65%).

Compound 5: Synthesis of compound 5 was carried out in an exactly samereaction sequence as in a synthesis of Example 31, where the compound 1in example 31 was substituted compound 4 in this example. [M+H]=438.

EXAMPLES 333-334

Examples 333 to 334 were synthesized using methodology described inExample 332. Example Structure [M + H] 333

452 334

478

EXAMPLE 335

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: Compound 2 is prepared in an exact same procedure asdescribed in synthesis of Example 333 where 3-fluorophenylacetonitrilereplaced 2-fluorophenylacetonitrile in synthesis of Example 335.

Compound 3: Compound 3 was prepared in a sequence described in synthesisof Example 31, where 4-(3-fluorophenyl)-4-cyanocyclohexanone 2 was usedinstead of compound 1 in example 31. [M+H]=438.

Examples 336 to 341 were synthesized using methodology described inExample 335. Example Structure [M + H] 336

438 337

452 338

452 339

464 340

478 341

478

EXAMPLE 342

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: Compound 2 is prepared in an exact same procedure asdescribed in synthesis of Example 332 where 4-fluorophenylacetonitrilereplaced the 2-fluorophenylacetonitrile.

Compound 3: Compound 3 was prepared in a sequence described in synthesisof Example 31, where compound 2 was used instead of compound 1 inexample 31. [M+H]=438.

EXAMPLES 343-348

Examples 343 to 348 were synthesized using methodology described inExample 342. Example Structure [M + H] 343

438 344

452 345

452 346

478 347

478 348

464

EXAMPLE 349

Synthesis:

Compound 1: The synthesis of 1 was described in Example 31.

Compound 2: The synthesis of 2 was described in Example 73.

Compound 3: A solution of 2 (20 mg, 0.041 mmol), 4-(aminomethyl)pyridine(10 mg, 0.10 mmol) in 1 ml of CH₃CN was stirred for 2 h at 65° C. Thereaction mixture was purified by preparative HPLC (described in asynthesis of Example 31) to yield 11.2 mg of the 3 as a colorless oil.Mass Spec [M+H]=509.

EXAMPLES 350-396

Examples 350 to 396 were synthesized using methodology described inExample 349. Ex- [M + ample Structure H] 350

567 351

567 352

567 353

620 354

509 355

548 356

524 357

566 358

496 359

537 360

537 361

485 362

523 363

527 364

529 365

537 366

495 367

529 368

515 369

539 370

595 371

531 372

581 373

523 374

523 375

418 376

539 377

567 378

538 379

632 380

607 381

646 382

600 383

647 384

588 385

588 386

588 387

608 388

608 389

574 390

574 391

609 392

653 393

618 394

628 395

590 396

579

EXAMPLE 397

Compound 1: Compound 1 is commercially available.

Compound 2: Compound 2 is prepared in an exact same procedure asdescribed in synthesis of Example 332 where 2-methoxyphenylacetonitrilereplaced the 2-fluorophenylacetonitrile in synthesis of Example 332.

Compound 3: Compound 3 was prepared in a sequence described in synthesisof Example 31, where 4-(2-methoxyphenyl)-4-cyanocyclohexanone 2 was usedinstead of compound 1 in example 31. [M+H]=450.

EXAMPLES 398-404

Examples 398 to 404 were synthesized using methodology described inExample 397. Example Structure [M + H] 398

476 399

476 400

490 401

490 402

464 403

450 404

464

EXAMPLE 405

Synthsis:

Compound 1: The synthesis of 1 was described in Example 388.

Compound 2: The synthesis of 2 was proceeded in a same proceduredescribed in Example 73.

Compound 3: A solution of 2 (40 mg, 0.083 mmol), 4-(aminomethyl)pyridine(20 mg, 0.20 mmol) in 1 ml of CH₃CN was stirred for 2 h at 65° C. Thereaction mixture was purified by preparative HPLC (described in asynthesis of Example 31) to yield 8.9 mg of the 3 as a colorless oil.Mass Spec [M+H]=539.

EXAMPLES 406-410

Examples 406 to 410 were synthesized using methodology described inExample 405. Exam- [M + ple Structure H] 406

596 407

596 408

538 409

538 410

539

EXAMPLES 411 AND 412

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 31.

Compound 2: To a specially designed vial for microwave reactor was addedcompound 1 (0.57 g, 2.3 mmol), Pd₂(dba)₃ (42 mg, 0.046 mmol), BINAP (79mg, 0.13 mmol) and t-BuONa (0.3 8 g, 2.3 mmol) in a portion. Thereaction vial was placed under vacuum to remove air. Toward the mixturewas, then, added 22 ml of degassed THF and the reaction vial was capped.The reaction mixture was placed in microwave reactor and heated for 20min at 180° C. The reaction mixture was cooled down and placed on columnchromatography (20-50% EtOAc/Hexane) to yield 0.62 g (72%) of thedesired product as oily solid.

Compound 3: Compound 2 (3.0 g, 8.0 mmol) was dissolved in THF (60 ml)and aq. HCl (10 ml), and the resulting solution was stirred for 4 h at35° C. THF was evaporated from the reaction mixture and the remainingaqueous solution was extracted with EtOAc (100 ml×2). The organic layerwas dried over MgSO4 and concentrated in vacuo to provide an oil (2.4g, >95%), which was identified as the desired product (1:1 mixture oftwo isomers) and subjected to the following reaction without any furtherpurification (>95% pure).

Compound 4: To a solution of compound 3 (1.2 g, 3.6 mmol) in 50 ml ofMeOH was added NH₄OAc (2.2 g, 27 mmol) and NaBH(OAc)₃ (0.98 g, 4.6 mmol)in a portion and the resulting solution was stirred at room temperaturefor 12 h. The reaction mixture was concentrated in vacuo, yielding oilyresidue, which was partitioned between EtOAc (200 ml) and brine (50 ml).The aqueous layer was further extracted with EtOAc (50 ml×2). Thecombined organic solution was dried over MgSO4 and concentrated in vacuoto yield an oil (1.2 g, >95%), which was identified as the desiredproduct and subjected to following reactions without furtherpurification (>90% pure).

Compound 5 and 6: Synthesis of compound 4 was carried out in an exactsame procedure as in synthesis of Example 31 using compound 4 (0.13 g,0.39 mmol), diphenyl cyanocarbonimidate (94 mg, 0.39 mmol) and 5 ml of 2N MeNH₂ in MeOH to produce 20.9 mg of compound 5 and 12.3 mg of compound6.

EXAMPLES 413-418

Examples 413 to 418 were synthesized using methodology described inExample 411. Example Structure [M + H] 413

427 414

427 415

453 416

453 417

439 418

439

EXAMPLE 419

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 153.

Compound 2: Compound 2 was prepared as a part of the library synthesis.The general procedure is following:

To a solution of the compound 1 (8.3 mg, 0.03 mmol) in 1 ml of1,2-dichloroethane was added 3-(trifluoromethyl)benzoyl chloride (20 μL,0.14 mmol) and 20 mg polymer-bound amine (PL-MPH resin, PolymerLaboratories) in a portion and the resulting mixture was swirled for 12h. Toward the reaction mixture was added polymer-bound resin PL-EDA (50mg, Polymer Laboratories) and the resulting mixture was swirled foradditional 5 h. The reaction mixture was then filtered and concentratedin speed-vac to yield 8.0 mg (0.020 mmol, 67%) of the desired product asa colorless oil. [M+H]=458.

EXAMPLES 420-449

Examples 420 to 449 were synthesized using methodology described inExamplee 419. Ex- am- [M + ple Structure H] 420

396 421

426 422

434 423

446 424

447 425

451 426

459 427

482 428

493 429

494 430

498 431

518 432

368 433

380 434

400 435

404 436

408 437

409 438

415 439

420 440

420 441

434 442

434 443

450 444

450 445

460 446

471 447

500 448

506 449

483

EXAMPLE 450

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 153.

Compound 2: Compound 2 was prepared as a part of the library synthesis.The general procedure is following:

To a solution of the acid (10 mg, 0.06 mmol) in 1 ml of DCM and 0.3 mlof DMF was added EDCI (11.5 mg, 0.06 mmol), and HOAt (8.2 mg, 0.06mmol). Toward the solution was added the compound 1 (11 mg, 0.04 mmol)in 1.2 ml of DCE-DMF (2:1). The reaction mixture was allowed to stir for12 h at 25° C. The reaction mixture was purified on prep-HPLC (seeExample 31) and concentrated in speed-vac to yield 10.8 mg (0.021 mmol,41%) of the desired product as a colorless oil.

EXAMPLES 451-562

Examples 451 to 562 were synthesized using methodology described inExample 450. Exam- [M + ple Structure H] 451

440 452

422 453

429 454

420 455

424 456

422 457

429 458

422 459

433 460

432 461

419 462

436 463

436 464

426 465

457 466

424 467

450 468

441 469

450 470

435 471

440 472

423 473

455 474

430 475

456 476

441 477

419 478

440 479

447 480

440 481

455 482

419 483

446 484

448 485

448 486

455 487

422 488

423 489

450 490

382 491

385 492

391 493

384 494

386 495

368 496

381 497

410 498

406 499

405 500

406 501

407 502

366 503

371 504

397 505

408 506

398 507

408 508

358 509

414 510

392 511

407 512

410 513

372 514

385 515

405 516

398 517

413 518

417 519

417 520

371 521

406 522

407 523

394 524

412 525

408 526

398 527

380 528

406 529

404 530

406 531

408 532

381 533

397 534

371 535

411 536

369 537

406 538

406 539

399 540

408 541

407 542

407 543

406 544

368 545

407 546

398 547

356 548

396 549

384 550

380 551

384 552

397 553

380 554

379 555

407 556

385 557

410 558

410 559

406 560

393 561

397 562

396

EXAMPLE 563

Compound 1: Synthesis of compound 1 is described in Example 31.

Compound 2: To a solution of 6-methoxysalicyclic acid (4.2 g, 25 mmol)in DCM (15 ml) and DMF (5 ml) was added EDCI (3.8 g, 1.3 25 mmol) andHOAt (33.4 g, 25 mmol) in a portion, respectively and the resultingsolution was stirred for 0.5 h. The mixture was added dropwise into asolution of compound 1 (4.7 g, 19 mmol) in 15 ml of DCM. The resultingsolution was stirred for 12 h at 25° C. The reaction mixture wasevaporated in vacuo to yield oily residue, which was purified on columnchromatography (20-50% EtOAc/Hexane) to provide the compound 2 (5.8 g,77%) as a colorless oil.

Compound 3: Compound 2 (5.8 g, 14.6 mmol) was dissolved in THF (80 ml)and 2N HCl—MeOH (40 ml). The mixture was allowed to stirr for 5 h at 50°C. The reaction mixture was then poured into EtOAc (300 ml) and theorganic layer was separated. The aqueous layer was extracted with EtOAc(50 ml×2). The combined organic layer was washed with aq. NaHCO₃, driedover Na₂SO₄ and concentrated in vacuo to provide the desired product(4.0 g, 80%), which was pure (>95%) and subjected to following reactionswithout any further purification.

Compound 4: The compound 3 (4.0 g, 11.3 mmol) was dissolved in MeOH (100ml) and stirred with NaBH₄ (0.50 g, 13 mmol) for 3 h at −78° C. HPLCanalysis showed the reaction was completed. The mixture was concentratedin vacuo to produce a white solid mixture, which was partitioned betweenEtOAc (200 ml) and brine (50 ml). The organic layer was dried overNa₂SO₄ and concentrated in vacuo to provide the alcohol (4.0 g, >95%) asan oil. The alcohol was dissolved in 30 ml of DCM and added pyridine (10ml) and methanesulfonyl chloride (1.1 ml, 13.6 mmol) at 0° C. Theresulting solution was stirred for 12 h at 25° C. The reaction wasquenched by adding water. Aqueous layer was further extracted with DCM(20 mL×2). The combined organic solution was washed with IN aq. HCl (30ml×2) and dried over Na₂SO₄. Concentration of the organic solutionprovided the desired product (5.2 g, 85% pure) as an oil, which wassubjected to following reaction without any further purification.

Compound 5: The compound 4 from above was dissolved in 20 ml of DMF andwas added NaN₃ (1.2 g, 15 mmol). The mixture was allowed to stir at 80°C. for 12 h. The reaction mixture was concentrated in vacuo to removeDMF and partitioned between EtOAc (100 ml) and brine (30 ml). Theaqueous layer was extracted with EtOAc (50 ml×2). The combined organicsolution was purified on CombiFlash (0 to 20% EtOAc/hexane) to yield thedesired product (2.0 g, 5.3 mmol, 53% for two steps) as a mixture ofcis- and trans-isomers (4:1) ratio.

Compound 6: The compound 5 was dissolved in 30 ml of MeOH and was addedcatalytic amount of 10% Pd/C. The mixture was placed under H₂ andstirred for 2 h at 25° C. The reaction mixture was filtered throughcelite assisted funnel. The filterate was concentrated in vacuo toprovide the desired product (1.4 g, 75%) as a colorless oil.

Compound 7: To a solution of the compound 6 (0.36 g, 1 mmol) in 10 ml ofisopropanol was added diphenyl cyanocarbonimidate (0.24 g, 1 mmol) andthe resulting solution was stirred for 5 h at 60° C. The reactionmixture was then concentrated in vacuo to provide oily residue, whichwas dissolved in 10 ml of MeNH2—MeOH solution and stirred for 5 h at 80°C. in a sealed tube. The reaction mixture was concentrated and purifiedon CombiFlash (20-100% EtOAc/Hexane) to yield the desired product (0.34g, 78%). [M+H]=436.

EXAMPLES 564-571

Examples 564 to 571 were synthesized using methodology described inExample 563. Example Structure [M + H] 564

422 565

422 566

450 567

450 568

476 569

476 570

462 571

462

EXAMPLES 572-573

Synthesis:

Compound 1: Synthesis of compound is described in Example 554.

Compound 2: To a solution of chloro sulfonylisocyanate (22 μl, 0.25mmol) in 1 ml of DCM was added chIoroethanol (17 μl, 0.25 mmol) at 0° C.The reaction was then allowed to stir for additional 4 h 25° C. Thereaction mixture was cooled down to 0° C. again and added 90 mg (0.25mmol) of compound 1 in 2 ml of DCM. The reaction mixture was stirred foradditional 12 h at 25° C. The reaction mixture was then diluted with 10ml of DCM and washed with 1N aq. HCl. Organic solution was dried overNa₂SO₄ and concentrated in vacuo to provide 130 mg of the desiredproduct, which was subjected to the following reaction without anyfurther purification.

Compound 3 and 4: Compound 2 (30 mg, 0.07 mmol) and4-(aminomethyl)pyridine (16 mL, 0.14 mmol) was diluted in 1 ml of CH₃CNand stirred for 12 h at 60° C. The reaction mixture was purified onpreparative HPLC (see Example 31) to provide 12.7 mg of Example 572 and3.3 mg of Example 573.

EXAMPLES 574-579

Examples 574 to 579 were synthesized using methodology described inExample 572. Example Structure [M + H] 574

525 575

525 576

540 577

540 578

506 579

506

EXAMPLE 580

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 31.

Compound 2: To a solution of compound 1 (0.20 g, 0.60 mmol) and Et₃N(0.5 ml) in 5 ml of DCM was added triphosgene (0.20 g, 0.67 mmol) in aportion and the resulting solution was stirred for 1 h at 25° C. Thereaction mixture was concentrated in vacuo to provide oily residue,which was purified on column chromatography (50% EtOAc/Hexane) to yield213 mg (0.58 g, >95%) of the desired product as an oil.

Compound 3: To a solution of the compound 2 (20 mg, 0.055 mmol) andbenzenesulfonamide (20 mg, 0.13 mmol) in 2 ml of acetone was added 0.2ml of 1N aq. NaOH in a portion and the resulting solution was stirredfor 1 h at 25° C. The solution was neutralized by adding 0.2 ml of aq.HCl and subjected to preparative HPLC see Example 31) to provide 10.1 mg(0.019 mmol, 30%) of the desired product as a white solid afterconcentration in speed-vac. [M+H]=522

EXAMPLES 581-590

Examples 581 to 590 were synthesized using methodology described inExample 580. Exam- [M + ple Structure H] 581

587 582

615 583

460 584

462 585

618 586

563 587

661 588

514 589

601 590

461

EXAMPLE 591

Synthesis:

Compound 1: Synthesis of compound 1 is described in Example 31.

Compound 2: To a solution of compound 1 (338 mg, 1.0 mmol) in 10 ml ofethanol was added dimethyl N-cyanodithioiminocarbonate (147 mg, 1.0mmol) in a portion and the resulting solution was stirred for 2 h at 70°C. HPLC and LC-MS analysis showed a completion of the reaction. Reactionmixture was concentrated in vacuo to provide an oil, which was subjectedto the following reaction without any further purification.

Compound 3: Compound 2 (40 mg, 0.09 mmol), NaOH (3.7 μg, 0.09 mmol) and4-chlorobenzenesulfonamide (34 mg, 0.18 mmol) were dissolved in 1 ml ofdioxane. The resulting solution was stirred for 15 min at 230° C. inmicrowave reactor. The reaction mixture was then cooled down andpurified in preparative HPLC (see Example 31) to yield 6.2 mg, (0.011mmol, 11%) of the deised product as a light gray solid uponconcentration of the elute. [M+H]=581.

EXAMPLES 592 and 593

Examples 592 and 593 were synthesized using methodology described inExample 591. Example Structure [M + H] 592

546 593

484

EXAMPLE 594

Synthesis:

Compound 1: Compound 1 is commercially available

Compound 2: To a solution of compound 1 (4.6 ml, 40 mmol) in 100 ml ofdry THF was added MeLi (2N in THF, 40 mmol) dropwise and the resultingsolution was stirred for 1 h at −78° C. Toward the solution was addedbromoepihydrin (3.4 ml, 40 mmol) in 50 ml of THF dropwise for 30 minperiod and the reaction mixture was stirred for another 1 h at −78° C.MeMgBr (3M in THF, 40 mmol) was added into the reaction mixture. Thereaction mixture was stirred for additional 12 h at ambient temperature.Reaction mixture was, then, diluted with EtOAc (250 mL) and washed withbrine (50 ml×3). Organic layer was dried over MgSO4 and concentrated invacuo to provide oily residue, which was purified on CombiFlash (0 to100% EtOAc/Hexane) to provide 5.6 g, (29 mmol, 73%) of the desiredproduct as a mixture of cis and trans isomers (4:1).

Compound 3: Toward solution of compound 2 (1.6 g, 9.0 mmol) in 30 ml ofTHF was added LAH (1.0 M in THF, 10 mmol) and the resulting solution wasstirred for 4 h at 70° C. The reaction was quenched by adding pieces ofice and mixture was filtered through celite. Concentration of filterateprovided an oil (1.5 g, >95%), which was subjected to following reactionwithout any further purification.

Compound 4: To a solution of the compound 3 (1.5 g, 9.0 mmol) in 50 mlof THF and Et₃N (2.0 ml) was added anisoyl chloride (1.3 ml, 9.0 mmol)dropwise and the resulting solution was stirred for 1 h at 25° C.Reaction mixture was then diluted with EtOAc (100 ml) and washed withbrine. Organic solution was dried over MgSO₄ and concentrated in vacuoto provide an oil, which was identified as bis-acylated product. Theproduct was dissolved in 30% aq. THF (20 ml) and LiOH (300 mg) was addedinto it. The resulting mixture was stirred for 12 h at 70° C. Themixture was diluted with EtOAc (50 ml) and washed with brine (30 ml).Concentration of the organic layer after drying over MgSO₄ provided oilyresidue, which was purified on CombiFlash to provide 1.5 g, (4.5 mmol,50% for two steps) of the desired product as a colorless oil.

Compound 5: Compound 4 was dissolved in 10 ml of DCM and 2 ml ofpyridine. Toward the solution was added methanesulfonyl chloride (1 ml,13 mmol) and the resulting solution was stirred for 2 h at 25° C. Thereaction mixture was diluted with EtOAc (200 ml) and washed with brine(30 ml×2). The organic layer was dried over MgSO₄ and concentrated invacuo to provide an oil, which was subjected to following reactionwithout any further purification.

Compound 6: Compound 5 and NaN₃ (1.3 g, 8.9 mmol) were dissolved in 10ml of DMF and the mixture was stirred for 5 h at 120° C. The reactionmixture was diluted with EtOAc (100 ml) and washed with brine (20 ml×3).The organic solution was dried over Na₂SO₄ and concentrated in vacuo toprovide an oil, which was purified CombiFlash (0-30% EtOAc/hexane) toprovide 1.1 g of the azide. The azide was dissolved in 20 ml of MeOH andcatalytic amount of 10% Pd—C was added into the solution. The reactionmixture was stirred under H₂ for 2 h. Reaction mixture was filteredthrough funnel (Whatman, 0.45 μm NYL) and concentrated in vacuo toprovide the desired product (1.1 g, 79% from compound 4) as a colorlessoil.

Compound 7: To a solution of compound 6 (180 mg, 0.58 mmol) in 5 ml ofisopropanol was added diphenyl cyanocarbonimidate (150 mg, 0.64 mmol)and the resulting solution was stirred for 2 h at 80° C. The reactionmixture was then concentrated in vacuo to provide oily residue It wasredissolved in 5 ml of 2N MeNH₂ in methanol and stirred for 5 h at 80°C. in a sealed tube. Progress of the reaction was monitored by HPLC. Thereaction mixture was concentrated in vacuo to yield oily residue, whichwas purified on CombiFlash (0-100% EtOAc/hexane) to provide 0.12 g (0.29mmol, 50%) of the desired product as a mixture of cis and trans isomers.[M+H]=410.

EXAMPLES 595-597

Examples 595 to 597 were synthesized using methodology described inExample 594. Example Structure [M + H] 595

424 596

424 597

396 598

436

EXAMPLE 599

cis-N-{4-[N′-Cyano-N″-ethyl-N-(2-methoxy-ethyl)-guanidino]-1-phenyl-cyclohexylmethyl}-2-methoxy-benzamide

Synthesis:

Compound 1: The synthesis of 1 has been previously described.

Compounds 2 and 3: To a solution of 1 (185 mg, 0.55 mmol) in1,2-dichloroethane (2 mL) was added 2-methoxyethylamine (0.048 mL, 0.55mmol) followed by sodium triacetoxyborohydride (163 mg, 0.77 mmol) andacetic acid (0.031 mL, 0.55 mmol), then the reaction stirred for 1.5hours. The reaction was quenched by addition of 1N NaOH (2 mL) thenextracted with Et₂O (3×4 mL). The combined organic extracts were washedwith brine (2 mL), dried (MgSO₄) filtered and concentrated in vacuo. Theresidue was chromatographed on silica, gradiently eluted using 1:1:98 to1:5:94 NH₄OH/MeOH/CHCl₃, to give 2 (80 mg, 37% yield, HPLC Rt 1.50 minusing Phenomenex 30×4.6 5u column over 2 min gradient using flow rate of5 mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA.Solvent B=90/10/0.1%. M+H=397.3) and 3 (66 mg, 30% yield, HPLC Rt 1.43min using Phenomenex 30×4.6 5u column over 2 min gradient using flowrate of 5 mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1%MeOH/H2O/TFA. Solvent B=90/10/0.1%. M+H=397.3) as white solids.

Compound 4: To a solution of the cis-isomer of the amine 2 (15 mg, 0.038mmol) in 2-propanol (1 mL) was added 1-cyano-3-ethyl-2-phenyl-isourea(36 mg, 0.19 mmol) then the reaction mixture was heated in a 75° C.oil-bath for 5 days. The solvent was removed under a stream of nitrogenthen the residue purified by prep TLC eluted with 5:20:75MeOH/EtOAc/hexanes to give 4 (9.5 mg, 51% yield, HPLC Rt 1.88 min usingPhenomenex 30×4.6 5u column over 2 min gradient using flow rate of 5mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%. M+H=492.3) as a white solid.

EXAMPLES 600-604

Examples 600 to 604 were prepared using methodology described in Example599. Ex. Structure Name [M + 1] 600

Cis-N-[4-(N′-Cyano-N″- ethyl-N-methyl-guanidino)- 1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 448 601

Cis-N-[4-(N-Benzyl-N′- cyano-N″-ethyl-guanidino)- 1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 524 602

Cis-N-[4-(N′-Cyano-N″- ethyl-N-pyridin-2-ylmethyl- guanidino)-1-phenyl-cyclohexylmethyl]-2-methoxy- benzamide 525 603

Cis-N-[4-(N′-Cyano-N″- ethyl-N-pyridin-3-ylmethyl- guanidino)-1-phenyl-cyclohexylmethyl]-2-methoxy- benzamide 525 604

Cis-N-[4-(N′-Cyano-N″- ethyl-N-furan-2-ylmethyl- guanidino)-1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 514

EXAMPLE 605

trans-N-{4-[N′-Cyano-N″-ethyl-N-(2-methoxy-ethyl)-guanidino]-1-phenyl-cyclohexylmethyl}-2-methoxy-benzamide

Synthesis:

Compound 3: The synthesis of compound 3 is described in Example 599.

Compound 5: To a solution of the trans-isomer of the amine 3 (15 mg,0.038 mmol) in 2-propanol (1 mL) was added1-cyano-3-ethyl-2-phenyl-isourea (36 mg, 0.19 mmol) then the reactionmixture was heated in a 75° C. oil-bath for 5 days. The solvent wasremoved under a stream of nitrogen then the residue purified by prep TLCeluted with 5:20:75 MeOH/EtOAc/hexanes to give 5 (10.8 mg, 58% yield,HPLC Rt 1.77 min using Phenomenex 30×4.6 5u column over 2 min gradientusing flow rate of 5 mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1%MeOH/H2O/TFA. Solvent B=90/10/0.1%. M+H=492.3) as a white solid.

EXAMPLES 606-609

Examples 606 to 609 were prepared using methodology described in Example605. Ex. Structure Name [M + 1] 606

Trans-N-[4-(N′-Cyano-N″- ethyl-N-methyl- guanidino)-1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 448 607

Trans-N-[4-(N′-Cyano-N″- ethyl-N-pyridin-2- ylmethyl-guanidino)-1-phenyl-cyclohexylmethyl]- 2-methoxy-benzamide 525 608

Trans-N-[4-(N′-Cyano-N″- ethyl-N-pyridin-3- ylmethyl-guanidino)-1-phenyl-cyclohexylmethyl]- 2-methoxy-benzamide 525 609

Trans-N-[4-(N′-Cyano-N″- ethyl-N-furan-2-ylmethyl- guanidino)-1-phenyl-cyclohexylmethyl]-2- methoxy-benzamide 514

EXAMPLE 610

cis-2-Methoxy-N-{4-[(2-methoxy-ethyl)-(morpholine-4-sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}-benzamide

Synthesis:

Compound 2: The synthesis of compound 2 is described in Example 599.

Compound 6: To a solution of the cis-isomer of the amine 2 (15 mg, 0.038mmol) in dimethylformamide (0.5 mL) was added triethylamine (0.007 mL,0.05 mmol) followed by morpholine-4-sulfonyl chloride (8.4 mg, 0.045mmol) and a catalytic amount of DMAP. The reaction was stirred for 5days then diluted with 50% EtOAc/hexanes (4 mL) and washed w/0.1N HCl (2mL) and brine (2 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by prep TLC eluted with3:25:72 MeOH/hexanes/EtOAc to give 6 (7.8 mg, 38% yield, HPLC Rt 2.30min using Phenomenex 30×4.6 5u column over 2 min gradient with 1 minhold time using flow rate of 5 mL/min. 0 to 100% Solvent B. SolventA=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. M+H=546.1) as a whitesolid.

EXAMPLES 611-615

Examples 611 to 615 were prepared using methodology described in Example610. Ex. Structure Name [M + 1] 611

Cis-2-Methoxy-N-{4- [methyl-(morpholine-4- sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}- benzamide 502 612

Cis-N-{4-[Benzyl- (morpholine-4-sulfonyl)- amino]-1-phenyl-cyclohexylmethyl}-2- methoxy-benzamide 578 613

Cis-2-Methoxy-N-{4- [(morpholine-4-sulfonyl)- pyridin-2-ylmethyl-amino]-1-phenyl- cyclohexylmethyl}- benzamide 579 614

Cis-2-Methoxy-N-{4- [(morpholine-4-sulfonyl)- pyridin-3-ylmethyl-amino]-1-phenyl- cyclohexylmethyl}- benzamide 579 615

Cis-N-{4-[Furan-2- ylmethyl-(morpholine-4- sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}-2- methoxy-benzamide 568

EXAMPLE 616

trans-2-Methoxy-N-{4-[(2-methoxy-ethyl)-(morpholine-4-sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}-benzamide

Compound 3: The synthesis of compound 3 is described in Example 599.

Compound 7: To a solution of the trans-isomer of the amine 3 (15 mg,0.038 mmol) in dimethylformamide (0.5 mL) was added triethylamine (0.007mL, 0.05 mmol) followed by morpholine-4-sulfonyl chloride (8.4 mg, 0.045mmol) and a catalytic amount of DMAP. The reaction was stirred for 5days then diluted with 50% EtOAc/hexanes (4 mL) and washed w/0.1N HCl (2mL) and brine (2 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by prep TLC eluted with3:25:72 MeOH/hesanes/EtOAc to give 7 (3.8 mg, 18% yield, HPLC Rt 2.20min using Phenomenex 30×4.6 5u column over 2 min gradient with 1 minhold time using flow rate of 5 mL/min. 0 to 100% Solvent B.

Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. M+H=546.1) as awhite solid.

EXAMPLES 617-621

Examples 617 to 621 were prepared using methodology described in Example616. Ex. Structure Name [M + 1] 617

Trans-2-Methoxy-N-{4- [methyl-(morpholine-4- sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}- benzamide 502 618

Trans-N-{4-[Benzyl- (morpholine-4- sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}-2- methoxy-benzamide 578 619

Trans-2-Methoxy-N-{4- [(morpholine-4- sulfonyl)-pyridin-2-ylmethyl-amino]-1-phenyl- cyclohexylmethyl}- benzamide 579 620

Trans-2-Methoxy-N-{4- [(morpholine-4- sulfonyl)-pyridin-3-ylmethyl-amino]-1-phenyl- cyclohexylmethyl}- benzamide 579 621

Trans-N-{4-[Furan-2- ylmethyl-(morpholine- 4-sulfonyl)-amino]-1-phenyl-cyclohexylmethyl}-2- methoxy-benzamide 568

EXAMPLE 622

N-(1-Benzyl-cyclohexylmethyl)-2-methoxy-benzamide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: A solution of cyclohexanecarbonitrile (6.14 g; 56.2 mmol) intetrahydrofuran (40 mL) was cooled to −78° C. under argon and treatedwith a 2M solution of lithium diisopropylamide in THF/n-heptane (36 mL;72 mmol). The cooling bath was removed and the reaction mixture wasallowed to stir at room temperature for 10 minutes. The reaction mixturewas cooled back to −78° C., treated with a solution of benzyl bromide(9.8 g; 57.3 mmol) in tetrahydrofuran (10 mL) and allowed to slowly warmto room temperature overnight. The reaction mixture was concentrated andthe residue was portioned between ethyl ether and a 10% aqueoushydrochloric acid solution. The organic layer was separated, washed withsaturated aqueous sodium chloride, dried (anhydrous sodium sulfate),filtered and concentrated. Column chromatography on silica gel using 9:1hexane:ethyl acetate as the eluent gave 11 g of compound 2 as a clearoil. Mass Spec [M+H]⁺=200.

Compound 3: A solution of compound 2 (3.8 g; 19.1 mmol) intetrahydrofuran (40 mL) was cooled to 0° C. and treated with lithiumaluminum hydride (3.8 g; 100.1 mmol) in portions. The reaction mixturewas allowed to slowly warm to room temperature overnight. The reactionmixture was carefully quenched with 2N sodium hydroxide (approximately 2mL), filtered through a plug of celite using ethyl acetate as theeluent, dried (anhydrous sodium sulfate), filtered and concentrated togive 3.8 g of compound 3 as a clear oil which was used in the next stepwith no additional purification. Mass Spec [M+H]⁺=204.

Title Compound: A solution of compound 3 (0.38 g; 1.8 mmol) intetrahydrofuran (20 mL) was treated with triethylamine (0.2 mL; 1.4mmol) followed by o-anisoyl chloride (0.34 g; 2.0 mmol) at roomtemperature. The reaction was allowed to stir 48 h at which time thesolvent was removed under reduced pressure. The residue was portionedbetween ethyl acetate and a 10% aqueous hydrochloric acid solution. Theorganic layer was separated, washed with saturated aqueous sodiumchloride, dried (anhydrous sodium sulfate), filtered and concentrated.Column chromatography on silica gel using 8:1 hexane:ethyl acetate asthe eluent gave 0.46 g ofN-(1-benzyl-cyclohexylmethyl)-2-methoxy-benzamide as a clear oil. MassSpec [M+H]⁺=338.

EXAMPLES 623-647

Examples 623-647 may be prepared using methodology described in Example622. Ex. Structure Name [M + H]⁺ 623

N-(1-Benzyl- cyclohexylmethyl)-2- trifluoromethyl-benzamide 376 624

N-(1-Benzyl- cyclohexylmethyl)-3- methoxy-benzamide 338 625

N-(1-Benzyl- cyclohexylmethyl)-3-cyano- benzamide 333 626

N-(1-Benzyl- cyclohexylmethyl)-2- fluoro-6-trifluoromethyl- benzamide394 627

N-(1-Benzyl- cyclohexylmethyl)-4- fluoro-2-trifluoromethyl- benzamide394 628

N-(1-Benzyl- cyclohexylmethyl)-2,4- difluoro- benzenesulfonamide 380 629

N-(1-Benzyl- cyclohexylmethyl)-2,5- dimethoxy- benzenesulfonamide 404630

N-(1-Benzyl- cyclohexylmethyl)-2,3- difluoro-benzamide 344 631

N-(1-Benzyl- cyclohexylmethyl)-4- methyl-benzamide 322 632

N-(1-Benzyl- cyclohexylmethyl)-2,4- difluoro-benzamide 344 633

N-(1-Benzyl- cyclohexylmethyl)-2,6- difluoro-benzamide 344 634

N-(1-Benzyl- cyclohexylmethyl)-2- chloro-nicotinamide 343 635

N-(1-Benzyl- cyclohexylmethyl)-2- methoxy-acetamide 276 636

N-(1-Benzyl- cyclohexylmethyl)-3,4- difluoro-benzamide 344 637

N-(1-Benzyl- cyclohexylmethyl)-2,4,5- trifluoro-benzamide 362 638

N-(1-Benzyl- cyclohexylmethyl)-5- fluoro-2-methyl-benzamide 340 639

N-(1-Benzyl- cyclohexylmethyl)-3- chloro-benzamide 342 640

N-(1-Benzyl- cyclohexylmethyl)- benzamide 308 641

N-(1-Benzyl- cyclohexylmethyl)-3,5- dimethoxy-benzamide 368 642

N-(1-Benzyl- cyclohexylmethyl)-2- trifluoromethoxy- benzenesulfonamide428 643

N-(1-Benzyl- cyclohexylmethyl)-2- phenyl-acetamide 322 644

N-(1-Benzyl- cyclohexylmethyl)-2-(4- fluoro-phenyl)-acetamide 340 645

N-(1-Benzyl- cyclohexylmethyl)-2-(4- methoxy-phenyl)-acetamide 352 646

2-Phenyl- cyclopropanecarboxylic acid (1-benzyl- cyclohexylmethyl)-amide348 647

N-(1-Benzyl- cyclohexylmethyl)-3- phenyl-propionamide 336

EXAMPLE 648

2-Methoxy-N-(1phenyl-cyclohexylmethyl)-nicotinamide

Compound 1: Compound 1 was prepared as described in Example 330.Synthesis:

Title Compound: A suspension of 2-methoxynicotinic acid (0.23 g; 1.5mmol) in methylene chloride (15 ml) was treated with oxalyl chloride(0.14 mL; 1.6 mmol) and 2 drops of N,N-dimethylformamide. The reactionmixture was allowed to stir at room temperature for 30 minutes at whichtime triethylamine (0.3 mL; 2.2 mmol) and compound 1 (0.315 g; 1.66mmol). After an additional 15 minutes of stirring the reaction mixturewas washed with water and saturated aqueous sodium chloride, dried(magnesium sulfate) and concentrated. The crude residue was purified bycolumn chromatography on silicia gel using 7:3 hexane:ethyl acetate asthe eluent to give 0.37 g of2-Methoxy-N-(1-phenyl-cyclohexylmethyl)-nicotinamide as a white solid.Mass Spec [M+H]⁺=325.

EXAMPLE 649

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 330.

Compound 2: A solution of compound 1 (1.2 g; 6.3 mmol) in anhydrousacetonitrile (30 mL) was treated with diphenyl N-cyanocarbonimidate (2.2g; 9.2 mmol) and heated at 80° C. for 4 h. The reaction mixture wasallowed to stand at room temperature overnight. The white precipitatethat formed was collected by filtration and washed with hexane toprovide 1.0 g of compound 2 as a white solid. Mass Spec [M+H]⁺=334.

Title Compound: Compound 2 (0.027 g; 0.08 mmol) was treated with a 2 Msolution of ethylamine in THF (0.5 mL; 1 mmol) and heated at 60° C. in ascrew cap vial overnight. The solvent and excess ethylamine was removedbe evaporation and the crude product was purified by preparativereverse-phase liquid chromatography to give 0.008 g of the titlecompound as a white solid. Mass Spec [M+H]⁺=285.

EXAMPLES 650-660

Example 650-660 were prepared using methodology described in Example649. [M + Ex. Structure H]⁺ 650

348 651

408 652

326 653

312 654

349 655

349 656

378 657

362 658

328 659

374 660

312

EXAMPLE 661

5-Benzyl-3-(1-phenyl-cyclohexylmethyl)-imidazolidine-2,4-dione

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 330.

Title Compound: A solution of compound 1 (0.255 g; 1.35 mmol) inanhydrous dichloromethane (8 mL) was treated with ethyl2-isocyanato-3-phenylpropionate (0.325 g; 0.38 mmol) and stirred at roomtemperature overnight. The solvent was removed by evaporation, theresidue was dissolved in ethanol (1 mL), 6N hydrochloric acid (0.5 mL)and water (0.5 mL) and the reaction mixture was heated to 50° C. After 3h at 50° C., additional 6N hydrochloric acid (1 mL) was added and thereaction mixture was heated at 65° C. overnight. The reaction mixturewas concentrated and the crude product was purified directly by columnchromatography on silica gel using 1:1 ethyl acetate:hexane as the theeluent to give 0.053 g of5-Benzyl-3-(1-phenyl-cyclohexylmethyl)-imidazolidine-2,4-dione as awhite solid. Mass Spec [M+H]⁺=363.

EXAMPLE 662

1-Isopropenyl-cyclohexanecarboxylic acid (3-phenyl-propyl)-amide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: To a solution of diisopropylamine (4.2 mL) in THF (30 mL) at0° C. was added n-BuLi in hexanes (1.6 M, 19 mL). After stirring for 30min., 20 the reaction mixture was cooled to −78° C. andcyclohexanecarbonitrile (1.09 g, 10 mmol) in THF (10 mL) was added dropwise. After 2 h, acetone (1.16 g, 20 mmol) was added. The reactionmixture was stirred from −78° C. to rt overnight, diluted with Et₂O (100mL), washed with 1N HCl, H₂O, brine and dried over anhydrous sodiumsulfate. Purification by flash chromatography (1:1, hexanes-Et₂O) gave1-(1-hydroxy-1-methyl-ethyl)-cyclohexanecarbonitrile (1.27 g, 76%) as acolorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 0.86-1.91 (8 H, m), 1.35(6 H, s), 2.01 (2 H, d, J=12.8 Hz), 3.65 (1 H, t, J=6.4 Hz). Mass Spec[M+H]⁺=168.1.

Compound 3: Compound 2 (530 mg, 3.17 mmol) and phosphorus oxychloride(11.7 g, 76.1 mmol) in CHCl₃ (12 mL) was heated at reflux for 18 h thencooled to rt. Water (75 mL) was slowly added. The aqueous layer wasextracted with CH₂Cl₂ (2×) and the combined extracts were dried overanhydrous sodium sulfate. Purification by flash chromatography (2:1,hexanes-CH₂Cl₂) gave 1-isopropenyl-cyclohexanecarbonitrile (1.27 g, 76%)as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.16-2.17 (13 H, m),4.96 (1 H, s), 5.11 (1 H, s). Mass Spec [M+H]⁺=150.1.

Compound 4: Compound 3 (280 mg, 1.87 mmol) and KOH (460 mg, 8.20 mmol)in ethylene glycol (3.7 mL) was heated at 185° C. for 18 h then cooledto rt. The reaction mixture was diluted with H₂O then extracted withEt₂O (2×). The aqueous phase was acidified with 6N HCl then extractedwith CH₂Cl₂ (3×) and dried over anhydrous sodium sulfate to give1-isopropenyl-cyclohexanecarboxylic acid (234 mg, 74%) as a waxy whitesolid. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.16-1.65 (9 H, m), 1.79 (3 H,s), 2.16-2.20 (2 H, m), 4.99 (2 H, s). Mass Spec [M+H]⁺=169.1.

Title Compound: Compound 4 was made to react with 3-phenylpropylamineusing methodology described in Example 74 to give1-isopropenyl-cyclohexanecarboxylic acid (3-phenyl-propyl)-amide. MassSpec [M+H]⁺=286.1.

EXAMPLES 663-665

Examples 663-665 were prepared using methodology described in Example662. Ex Structure Name [M + H]⁺ 663

1-Isopropenyl- cyclohexanecarboxylic acid (3,3-diphenyl- propyl)-amide362 664

1-Isopropenyl- cyclohexanecarboxylic acid (biphenyl-3- ylmethyl)-amide334 665

1-Isopropenyl- cyclohexanecarboxylic acid isoquinolin-1- ylamide 295

EXAMPLE 666

1-Isopropyl-cyclohexanecarboxylic acid (3-phenyl-propyl)-amide

Synthesis:

Compound 1: Compound 1 may be prepared as described in Example 662.

Title Compound: Compound 1 (33 mg, 0.12 mmol) and 10% Pd on carbon (30mg), in EtOH (1 mL) was stirred under hydrogen for 18 h. The reactionmixture was filtered over celite and concentrated to give1-isopropyl-cyclohexanecarboxylic acid (3-phenyl-propyl)-amide (33 mg,100%) as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 0.86 (6 H, d,J=6.8 Hz), 1.00-1.40 (5 H, m), 1.50-1.65 (4 H, m), 1.80-1.90 (4 H, m),2.67 (2 H, t, J=7.5 Hz), 3.33-3.48 (2 H, m), 5.59 (1 H, s), 7.17-7.31 (5H, m). Mass Spec [M+H]⁺=288.

EXAMPLES 667-668

Examples 667-668 were prepared using methodology described in Example666. Ex Structure Name [M + H]⁺ 667

1-Isopropyl- cyclohexanecarboxylic acid (3,3-diphenyl-propyl)- amide 364668

1-Isopropyl- cyclohexanecarboxylic acid (biphenyl-3- ylmethyl)-amide 336

EXAMPLE 669

N-(1-Isopropenyl-cyclohexylmethyl)-2-methoxy-benzamide

Synthesis:

Compound 1: Compound 1 may be prepared as described in Example 662.

Compound 2: To Compound 1 (100 mg, 0.67 mmol) in THF (3 mL) cooled to 0°C. was added LAH (102 mg, 2.68 mmol). The reaction mixture was stirredfrom 0° C. to rt overnight then quenched with H₂O (0.1 mL), 15% NaOH(0.1 mL), H₂O (0.3 mL), filtered then dried over anhydrous sodiumsulfate to give (1-isopropenyl-cyclohexyl)-methylamine (63 mg, 61% as acolorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.05-1.80 (15 H, m), 2.46(2 H, s), 4.76 (1 H, s), 5.07 (1 H, s). Mass Spec [M+H]⁺=154.

Title Compound: Compound 2 was made to react with o-anisoyl chlorideusing methodology described in Example 1 to provideN-(1-isopropenyl-cyclohexylmethyl)-2-methoxy-benzamide. Mass Spec[M+H]⁺=288.

EXAMPLE 670

Example 670 was prepared using methodology described in Example 669.[M + Ex Structure Name H]⁺ 670

N-Bicyclo- hexyl-1′-en- 1-ylmethyl- 2-methoxy- benzamide 328

EXAMPLE 671

N-(1-Isopropyl-cyclohexylmethyl)-2-methoxy-benzamide

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 669.

Title Compound: The title compound was prepared using methodologydescribed in Example 669. Mass Spec [M+H]⁺=290.

EXAMPLE 672

2-Methyl-3-(1-phenyl-cyclohexylmethyl)-3H-imidazo[4,5-b]pyridine

Synthesis:

Compound 1: Compound 1 may be prepared as described in Example 330.

Compound 2: A solution of compound 1 (1.21 g; 6.39 mmol) in anhydroustetrahydrofuran (30 mL) was treated with N,N-diisopropylethylamine (1mL; 5.73 mmol) and 2-bromo-3-nitro-pyridine (1.18 g; 5.81 mmol). Thereaction mixture was heated at 60° C. for 21 h. The solvent was removedunder reduced pressure and the residue was treated with ethyl acetateand 10% aqueous hydrochloric acid. The organic layer was separated,washed with saturated aqueous sodium chloride, dried (anhydrous sodiumsulfate), filtered and concentrated. The product was purified byrecrystalization from a minimum amount of ethyl acetate to provide 1.3 gof (3-nitro-pyridin-2-yl)-(1-phenyl-cyclohexylmethyl)-amine as light tansolid. Mass Spec [M+H]⁺=312.

Compound 3: A solution of compound 2 (0.96 g; 3.1 mmol) intetrahydrofuran (25 mL) and methanol (10 mL) was cooled to 0° C. underargon. Sodium borohydride (0.62 g; 16.4 mmol) and nickel(II) chloride(0.06 g; 0.46 mmol) were added and the cooling bath was removed. Thereaction mixture was stirred at room temperature for 1 h at which TLCanalysis indicated no starting material remained. The reaction wasquenched with 2N NaOH (5 mL) and the volatile components were removedunder reduced pressure. The residue was treated with ethyl acetate and1N NaOH. The organic layer was separated, washed with saturated aqueoussodium chloride, dried (anhydrous sodium sulfate), filtered andconcentrated. The product was purified by recrystalization from aminimum amount of ethyl acetate and several drops of methanol to provide0.47 g of (N2-(1-phenyl-cyclohexylmethyl)-pyridine-2,3-diamine as awhite solid. Mass Spec [M+H]⁺=282.

Title Compound: Compound 3 (0.087 g; 0.31 mmol), acetic acid (1 mL) andEEDQ (0.094 g; 0.38 mmol) were combined and heated to 120° C. underargon for 4 h. The reaction mixture was cooled to room temperature,diluted with acetonitrile and water, and purified by preparativereverse-phase liquid chromatography to provide 0.01 g of2-methyl-3-(1-phenyl-cyclohexylmethyl)-3H-imidazo[4,5-b]pyridine as awhite solid. Mass Spec [M+H]⁺=306.

EXAMPLE 673

3-(1-Phenyl-cyclohexylmethyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 672.

Title Compound: A solution of compound 1 (0.095 g; 0.34 mmol) indichloromethane (2 mL) was treated with triethylamine (0.05 mL; 0.36mmol) and diphosgene (0.041 mL; 0.34 mmol) and allowed to stir at roomtemperature for 2 h.

Additional dichloromethane and 5% aqueous hydrochloric acid was added tothe reaction mixture. The organic layer was separated, washed withsaturated aqueous sodium chloride and concentrated. The residue wasdissolved in an acetonitrile/water mixture and lyophilized to provide0.04 g of3-(1-phenyl-cyclohexylmethyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one asa white solid. Mass Spec [M+H]⁺=308.

EXAMPLE 674

{2-[(1-Phenyl-cyclohexylmethyl)-amino]-pyridin-3-yl}-methanol

Synthesis:

Compound 1: Compound 1 may be prepared as described in Example 330.

Compound 2: Compound 2 may be prepared using methodology described inExample 672 using ethyl 2-chloronicotinate instead of2-bromo-3-nitro-pyridine. The product was isolated as a colorless oil bycolumn chromatography on silica gel using 8:2 hexane:ethyl acetate asthe eluent. Mass Spec [M+H]⁺=339.

Title Compound: A solution of compound 2 (0.15 g; 0.43 mmol) intetrahydrofuran (6 mL) was cooled to 0° C. under argon. Lithium aluminumhydride (0.073 g; 19.2 mmol) was added in 10 mg portions. After theaddition was complete the cooling bath was removed and the reactionmixture was allowed to stir at room temperature for 0.5 h. The reactionwas quenched with water (1 mL) and the reaction mixture was concentratedunder reduced pressure. The residue was treated with ethyl acetate andsaturated aqueous sodium bicarbonate. The organic layer was separated,washed with saturated aqueous sodium chloride, dried (anhydrous sodiumsulfate), filtered and concentrated. Column chromatography on silica gelusing 1:1 hexane:ethyl acetate as the eluent gave 0.06 g of{2-[(1-phenyl-cyclohexylmethyl)-amino]-pyridin-3-yl}-methanol as a whitefoam. Mass Spec [M+H]⁺=297.

EXAMPLE 675

N-(4-Methyl-pyridin-2-yl)-3-phenyl-N-(1-phenyl-cyclohexylmethyl)-propionamide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: Compound 2 may be prepared using methodology described inExample 325 using 4-methyl-pyridin-2-ylamine instead ofisoquinolin-1-ylamine. The product was purified by recyrstalization froma minimum amount of ethyl acetate, several drops of methanol and severaldrops of hexane to give compound 2 as a brown powder. Mass Spec[M+H]⁺=295.

Compound 3: Compound 3 may be prepared using methodology described inExample 325. The product was isolated as a colorless oil. Mass Spec[M+H]⁺=281.

Title compound: A solution of compound 3 (0.035 g; 0.13 mmol) inacetonitrile (2 mL) was treated with polystyrene-diisopropylethylamine(PS-DIEA) (200 mg) and hydrocinnamoyl chloride (0.05 g; 0.3 mmol). Thereaction was allowed to shake for 6 h. The reaction mixture was purifieddirectly by preparative reverse phase liquid chromatography to provide0.02 g ofN-(4-methyl-pyridin-2-yl)-3-phenyl-N-(1-phenyl-cyclohexylmethyl)-propionamideas a white solid. Mass Spec [M+H]⁺=413.

EXAMPLES 676-680

Examples 675-680 were prepared using methodology described in Example675. Ex Structure Name [M + H]⁺ 676

N-(4-Methyl-pyridin-2- yl)-3-phenyl-N-(1-phenyl- cyclohexylmethyl)-acrylamide 411 677

2-Methoxy-N-(4-methyl- pyridin-2-yl)-N-(1- phenyl- cyclohexylmethyl)-benzamide 415 678

N-(4-Methyl-pyridin-2- yl)-2-phenyl-N-(1-phenyl- cyclohexylmethyl)-acetamide 399 679

N-(4-Methyl-pyridin-2- yl)-N-(1-phenyl- cyclohexylmethyl)- benzamide 385680

N-(4-Methyl-pyridin-2- yl)-N-(1-phenyl- cyclohexylmethyl)- acetamide 323

EXAMPLE 681

3-Phenyl-N-(1-phenyl-cyclohexylmethyl)-N-pyrimidin-2-yl-propionamide

Synthesis:

Compound 1: Compound 1 may be prepared as described in Example 330.

Compound 2: Compound 2 may be prepared using methodology described inExample 672. Mass Spec [M+H]⁺=268.

Compound 3: A solution of compound 2 (0.1 g; 0.37 mmol) intetrahydrofuran (2 mL) was treated with triethylamine (0.1 mL; 0.72mmol) and hydrocinnamoyl chloride (0.08 g; 0.47 mmol). The reactionmixture was allowed to stir at room temperature for 48 h. The solventwas removed by evaporation and the residue purified directly bypreparative reverse phase liquid chromatography to provide 0.018 g of3-phenyl-N-(1-phenyl-cyclohexylmethyl)-N-pyrimidin-2-yl-propionamide asa white solid. Mass Spec [M+H]⁺=400.

EXAMPLE 682

2-Methoxy-N-[2-(1-phenyl-cyclohexyl)-ethyl]-benzamide

Synthesis:

Compound 1: Compound 1 is commercially available.

Compound 2: To a suspension of LAH (3.8 g, 0.1 mol) cooled to 0° C. wasslowly added 1-phenyl-cyclohexanecarboxylic acid (10.2 g, 50.0 mmol).After stirring from 0° C. to rt overnight, the reaction mixture wasquenched with H₂O (3.8 mL), 15% NaOH (3.8 mL), H₂O (11.4 mL) andfiltered. The salt was washed with Et₂O and the combined organic phasedried over anhydrous sodium sulfate to give(1-phenyl-cyclohexyl)-methanol (8.48 g, 89%) as a white solid. ¹H NMR(CDCl₃, 300 MHz) δ (ppm) 1.30-1.70 (9 H, m), 2.15-2.36 (2 H, m), 3.51 (2H, s), 7.20-7.27 (1 H, m), 7.34-7.41 (4 H, m). Mass Spec [M+H]⁺=191.1.

Compound 3: To compound 2 (5.0 g, 26.3 mmol) in CH₂Cl₂ (50 mL) was added13.4 g (31.6 mmol) of Dess-Martin periodinane. After 2 h, sodiumthiosulfate (58 g) followed by sat. NaHCO₃ (200 mL) was added. Afterstirring for 1 h, the reaction mixture was diluted with EtOAc thenwashed with H₂O , brine and dried over anhydrous sodium sulfate.Purification by flash chromatography (3:1, hexane-EtOAc) gave1-phenyl-cyclohexanecarbaldehyde (4.47 g, 90%) as a colorless oil.

Mass Spec [M+H]⁺=189.1.

Compound 4: To compound 3 (4.47 g, 23.7 mmol) in PhCH₃ (130 mL) at 0° C.was added 36 mL of diethylaluminium cyanide (1.0 M/PhCH₃). Afterstirring for 3 h at 0° C. the reaction mixture was quenched with sat.Rochelle's salt and stirred at rt for 2 h. The aqueous layer wasextracted with CH₂Cl₂ (2×) and the combined extracts dried overanhydrous sodium sulfate. Hydroxy-(1-phenyl-cyclohexyl)-acetonitrile wasused without purification. Mass Spec [M+H]⁺=216.1.

Compound 5: To compound 4 (23.7 mmol) in CH₂Cl₂ (80 mL) was added 5.07 g(28.4 mmol) of 1,1′-thiocarbonyldiimidazole followed by DMAP (0.579 g,4.74 mmol). After stirring overnight the reaction mixture was washedwith H2O and dried over anhydrous sodium sulfate. Purification by flashchromatography (3:1, hexane-EtOAc) gave imidazole-1-carbothioic acidO-[cyano-(1-phenyl-cyclohexyl)-methyl] ester (6.27 g, 81%) as ayellowsyrup. Mass Spec [M+H]⁺=326.1.

Compound 6: Compound 5 (6.27 g, 19.3 mmol), Bu₃SnH (16.8 g, 57.8 mmol)and AIBN (0.63 g, 3.85 mmol) in PhCH₃ (100 mL) was heated at reflux for1 h then concentrated. Purification by flash chromatography (hexane then4:1, hexane-EtOAc) gave (1-phenyl-cyclohexyl)-acetonitrile (3.84 g,100%) as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.20-1.80 (8H, m), 2.25-2.49 (2 H, m), 2.49 (2 H, s), 7.35-7.46 (5 H, m). Mass Spec[M+H]⁺=210.1.

Compound 7: To compound 6 (500 mg, 2.51 mmol) in THF (10 mL) cooled at0° C. was slowly added 382 mg (10.04 mmol) of LAH. After stirring from0° C. to rt overnight, the reaction mixture was cooled to 0° C. thenquenched with H₂O (0.38 mL), 15% NaOH (0.38 mL), H₂O (1.14 mL) andfiltered. The salt was washed with Et₂O and the combined organic phasedried over anhydrous sodium sulfate to give2-(1-phenyl-cyclohexyl)-ethylamine (510 mg, 100%) as a colorless oil.Mass Spec [M+H]⁺=204.2

Title Compound: 2-Methoxy-N-[2-(1-phenyl-cyclohexyl)-ethyl]-benzamidemay be prepared using methodology described in Example 1. Mass Spec[M+H]⁺=338.

EXAMPLE 683

Example 683 was prepared using methodology described in Example 682 [M +Ex structure Name H]⁺ 683

2-Hydroxy-6- methoxy-N-[2- (1-phenyl- cyclohexyl)- ethyl]- benzamide 354

EXAMPLE 684

N-(2-Methoxy-phenyl)-2-(1-phenyl-cyclohexyl)-acetamide

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 682.

Compound 2: Compound 1 (3.58 g, 17.96 mmol) and KOH (4.42 g, 78.77 mmol)in ethylene glycol (35 mL) was heated at 170° C. for 48 h then cooled tort. The reaction mixture was diluted with H₂O then extracted with Et₂O(2×). The aqueous phase was acidified with 6N HCl then extracted withEt₂O (3×) and dried over anhydrous sodium sulfate to give(1-phenyl-cyclohexyl)-acetic acid (3.43 mg, 88%) as a tan solid. MassSpec [M+H]⁺=219.1.

Title Compound: To compound 2 (50 mg, 0.23 mmol) in CH₂Cl₂ (1 mL) wasadded 24 μL (0.27 mmol) of oxalyl chloride followed by one drop of DMF.After 1 h, o-anisidine (28 mg, 0.23 mmol) followed by Et₃N (97 μL, 0.27mmol) was added. After stirring for 3 h, the reaction mixture wasdiluted with EtOAc, washed with 1 N HCl, 1 N NaOH, H₂O, brine and driedover anhydrous sodium sulfate. Purification by flash chromatography(9:1, hexane-EtOAc) gaveN-(2-methoxy-phenyl)-2-(1-phenyl-cyclohexyl)-acetamide (37 mg, 50%) as awhite solid. Mass Spec [M+H]⁺=324.

EXAMPLE 685

2-(1-Phenyl-cyclohexylmethyl)-1H-benzoimidazole

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 684.

Compound 2: To compound 1 (100 mg, 0.046 mmol) in CH₂Cl₂ (2 mL) wasadded 48 μL (0.54 mmol) of oxalyl chloride followed by one drop of DMF.After 1.5 h, the resulting acid chloride was added to a solution of1,2-phenylenediamine (28 mg, 0.23 mmol) Et₃N (190 μL, 0.1.38 mmol) wasadded. After stirring for 1 h, the reaction mixture was diluted withEtOAc, washed with 1 N HCl, 1 N NaOH, H₂O, brine and dried overanhydrous sodium sulfate.N-(2-Amino-phenyl)-2-(1-phenyl-cyclohexyl)-acetamide was used in nextstep without purification.

Title Compound: Compound 2 (0.46 mmol) in glacial AcOH (2 mL) was heatedat 100° C. for 2 h then cooled to rt. The reaction mixture wasconcentrated and the residue purified by flash chromatography (1:1,hexane-EtOAc) to give 2-(1-phenyl-cyclohexylmethyl)-1H-benzoimidazole(73 mg, 54%) as a white solid. Mass Spec [M+H]⁺=291.

EXAMPLES 686-687

Examples 686-687 were prepared using methodology described in Example685. [M + Ex structure Name H]⁺ 686

1-Methyl-2-(1- phenyl-cyclo- hexylmethyl)- 1H-benzo- imidazole 305 687

7-Methoxy-2- (1-phenyl- cyclohexyl- methyl)-1H- benzo- imidazole 321

EXAMPLE 688

2-(1-Phenyl-cyclohexylmethyl)-3H-quinazolin-4-one

Synthesis:

Compound 1: Compound 1 was prepared as described in Example 684.

Compound 2: To compound 2 (75 mg, 0.0.34 mmol) in CH₂Cl₂ (1 mL) wasadded 36 μL (0.0.41 mmol) of oxalyl chloride followed by one drop ofDMF. After 1 h, anthranilamide (46 mg, 0.0.34 mmol) followed by Et₃N(150 μL, 1.02 mmol) was added. After stirring overnight, the reactionmixture was diluted with EtOAc, washed with 1 N HCl, 1 N NaOH, H₂O,brine and dried over anhydrous sodium sulfate. Purification by flashchromatography (1:1, hexane-EtOAc) gave2-[2-(1-phenyl-cyclohexyl)-acetylamino]-benzamide (78 mg, 68%) as awhite solid. Mass Spec [M+H]⁺=337.2.

Title Compound: The amide (73 mg, 0.217 mmol) in EtOH (1 mL) and 2N NaOH(1 mL) was heated at 80° C. for 1 h. The reaction mixture wasconcentrated, extracted with CH₂Cl₂ (3×) then dried over anhydroussodium sulfate. Purification by flash chromatography (1:1, hexane-EtOAc)gave 2-(1-phenyl-cyclohexylmethyl)-3H-quinazolin-4-one (66 mg, 96%) as awhite solid. Mass Spec [M+H]⁺=319.2.

EXAMPLE 689

1-(1-Phenyl-cyclohexylmethoxy)-isoquinoline

Synthesis:

Compound 1: Compound 1 was prepared using methodology described inExample 682.

Title Compound: A solution of compound 1 (0.23 g; 1.23 mmol) intetrahydrofuran (10 mL) was cooled to 0° C. under argon. Sodium hydride(0.080 g; 3.3 mmol) was slowly added in 5-10 mg portions. After theaddition was complete the reaction mixture was allowed to stir at 0° C.for 0.25 h and 1-chloroisoquinoline (0.32 g; 2.0 mmol) was added. Thereaction mixture was allowed to slowly warm to room temperatureovernight. Additional sodium hydride (0.080 g; 3.3 mmol) was added andthe reaction mixture was heated at 60° C. for 7 h. The solvent wasremoved by evaporation and the residue was purified by columnchromatography on silica gel using 8:2 hexane:ethyl acetate as theeluent to provide 0.02 g of 1-(1-phenyl-cyclohexylmethoxy)-isoquinoline.Mass Spec [M+H]⁺=318.

EXAMPLES 690-694

Examples 690-694 were prepared using methodology described in Example325. Ex structure Name [M + H]⁺ 690

(1-Isopropenyl- cyclohexylmethyl)- isoquinolin-1-yl-amine 281 691

1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid isoquinolin-1- ylamide349 692

1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid isoquinolin-1- ylamide349 693

[1-(3-Fluoro-phenyl)- cyclohexylmethyl]- isoquinolin-1-yl-amine 335 694

[1-(2-Fluoro-phenyl)- cyclohexylmethyl]- isoquinolin-1-yl-amine 335

1. A compound of Formula I

enantiomers, diastereomers, solvates or salts thereof wherein: m is 1; pis 1 or 2; R¹ is

 —CO₂H, —C(O)R^(8c), —NR⁶R⁷, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, halo,perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted alkyl, optionally subsituted alkenyl, oroptionally subsituted alkynyl; R^(1a) is H, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; or R¹ and R^(1a)together form oxo; or R¹ and R^(1a) together with the carbon atom towhich they are attached combine to form an optionally substitutedspiro-fused heterocyclo group;  or R¹ and R^(1a) together combine toform a group

 R² is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may beoptionally independently substituted with one or more groups T¹, T² orT³; J is a bond or C₁₋₄ alkylene optionally independently substitutedwith one or more groups T^(1a), T^(2a) or T^(3a); R³ is

R⁴ is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, orheteroaryl any of which may be optionally independently substituted withone or more groups T^(1b), T^(2b) or T^(3b); R^(4a) is R⁴ or OR⁴; R⁵ is—NR^(6a)R^(7a), or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl,alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or(heterocyclo)alkyl, any of which may be optionally independentlysubstituted with one or more groups T^(1c), T^(2c) or T^(3c); R⁶,R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8a1), R^(8a2), R^(8a3), R^(8a4),R^(8a5) and R⁹ are independently H, alkyl, hydroxy, alkoxy, aryloxy,heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl,(aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl,(cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl,heterocyclo, (heterocyclo)alkyl, -C(O)R², -CO₂R¹², or —C(O)—NR¹²KR¹³,any of which may be optionally independently substituted with one ormore groups T^(1d), T^(2d) or T^(3d); or R⁶, R⁷, or R^(6a) and R^(7a)together with the nitrogen atom to which they are attached may combineto form a saturated or unsaturated 4 to 8 membered ring optionallyindependently substituted with one or more groups T^(1d), T^(2d) orT^(3d); or one of R⁶ or R⁶, may combine with one of R⁸, R^(8a), or R⁹ toform a saturated or unsaturated 5 to 8 membered ring optionallyindependently substituted with one or more groups T^(1d), T^(2d) orT^(3d). or one of R^(6a) or R^(7a), may combine with R^(8a) to form asaturated or unsaturated 5 to 8 membered ring optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d) R^(8b) isindependently H, alkyl, aryl, cyano, nitro, acyl or —SO₂(alkyl); R^(8c)is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloheteroalkyl, heteroaryl, amino or alkoxy; R^(8d) is R⁴, COR⁴,CO₂R⁴, SO₂R⁴, CONR⁶R⁷, or SO₂—NR⁶R⁷; R¹⁰ R^(10a), R¹¹ and R^(11a) areindependently H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo,hydroxy, (hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl,heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl,(cycloalkyl)alkyl, or cyano any of which may be optionally independentlysubstituted on available atoms with one or more groups T^(1e), T^(2e) orT^(3e); or R¹⁰ and R^(10a), or R¹¹ and R^(11a) may combine to form oxo;or R^(10a) may combine with R^(11a) to form a bond; or R¹⁰ may combinewith R⁹ to form a saturated or unsaturated ring; R¹² and R¹³ areindependently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,(heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl,heterocyclo, or (heterocyclo)alkyl any of which may be optionallyindependently substituted with one or more groups groups T^(1f), T^(2f)or T^(3f) or R¹² and R¹³ together with the nitrogen atom to which theyare attached may combine to form a saturated or unsaturated ring whichmay be optionally independently substituted with one or more groupsgroups T^(1f), T^(2f) or T^(3f); W is ═NR^(8a2), ═N—CO₂R^(8a2),═N—COR^(8a2), ═N—CN, or ═N—SO₂R^(8a2); X is

Z, Z¹ and Z² are independently ═O, ═S, ═NR^(8a4) or ═N—CN; R¹⁴ isindependently

where q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; R^(X) is one or more optional substituents, attached toany available ring carbon atom, independently selected from T^(1g),T^(2g) or T^(3g); T^(1-1g), T^(2-2g), and T^(3-3g) are are eachindependently (1) hydrogen or T⁶, where T⁶ is (i) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i)which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more (preferably 1 to 3) of the following groups(2) to (13) of the definition of T^(1-1g), T^(2-2g) and T^(3-3g), (2)—OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶,where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶, (6) halo,(7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸ (10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11)-T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13) oxo, T⁴ and T⁵ are eachindependently (1) a single bond, (2) -T¹¹-S(O)_(t)-T¹², (3)-T¹¹-C(O)-T¹², (4) -T¹¹-C(S)-T¹², (5) -T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-, (7)-T¹¹-O—C(O)-T¹²-, (8) -T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-, or(10) -T¹¹-C(O)—C(O)-T¹²- T⁷, T⁸, T⁹, T^(9a) and T¹⁰ (1) are eachindependently hydrogen or a group provided in the definition of T⁶, or(2) T⁷ and T⁸ may together be alkylene or alkenylene, completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached, which ring is unsubstituted or substituted withone or more groups listed in the definition of T^(1-1g), T^(2-2g) andT^(3-3g), or (3) T⁷ or T⁸, together with T⁹, may be alkylene oralkenylene completing a 3- to 8-membered saturated or unsaturated ringtogether with the nitrogen atoms to which they are attached, which ringis unsubstituted or substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹and T¹⁰ together with the nitrogen atom to which they are attached maycombine to form a group —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are eachindependently H or a group provided in the definition of T⁶; T¹¹ and T¹²are each independently (1) a single bond, (2) alkylene, (3) alkenylene,or (4) alkynylene; provided that (i) R² is other than

 T when conditions (a) and (b) are both met (a) -J-R³ is

(b) R¹ is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy,heteroaryloxy, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, —OC(═O)CCl₃, —SO₂(alkyl),—SO₂(aryl), —SO₂(arylalkyl), —CO₂H, —C(═O)(alkyl), —CO₂(alkyl),—C(═O)NR^(6*)R^(7*), —NR^(6*)R^(7*), —OC(═O)NR^(6*)R^(7*), —N₃,—N(R⁸)C(O)NR^(6*)R^(7*), —OC(═O)OR⁴ —OC(═O)R⁴, or —N(H)S(O₂)R⁴, or R¹and R^(1a) combine to form oxo; or R¹ and R^(1a) together with thecarbon atom to which they are attached combine to form a Spiro fusedheterocylo group, or R¹ and R^(1a) together combine to form a group

 where R^(6*)and R^(7*)are each independently H, aryl, —C(O)aryl,—CO₂aryl, alkyl, —C(O)alkyl, —CO₂alkyl, —S(O)_(u)alkyl,—C(O)S(O)_(u)alkyl, —S(O)_(u)aryl, —C(O)S(O)_(u)aryl, or heterocyclo;R^(5a) is

R^(8a) H, or alkyl; and u is 0, 1, 2or 3; (ii) R² is other than thienylwhen conditions (c) and (d) are both met (c) -J-R³ is —NR^(6b)R^(7b)where R^(6b) and R^(7b) are independently H, alkyl, cycloalkyl, orR^(6b) and R^(7b) combine to form an N-containing cyclic groupcontaining at least one double bond; and (d) R¹ is alkyl, cycoalkyl,alkenyl, alkynyl, alkoxy, amino or cyano (iii) said compound is otherthan a compound of the formula

 where R^(1c) is —OC(O)NHR^(7c), or —OC(O)R^(4b); R^(2a) is alkyl orphenyl; R^(3a) is

 R^(4b) is alkyl; R^(5b) is —NHR^(7d) or benzyl substituted with one tothree groups independently selected from halo, alkyl or alkoxy R^(7c) isH, alkyl, phenyl or benyl; R^(7d) is phenyl substituted with one tothree groups independently selected from halo, alkyl or alkoxy; R^(Xa)is hydroxy, —OC(O)NHR^(7c) or —OC(O)^(4b); R^(Xb) and R^(Xc) areindependently H or alkyl; n* is 1 to 4; n** is 0 to 3; (iv) R² is otherthan phenyl when conditions (e) and (f) are both met (e) R¹ is alkyl,alkoxy, or phenyl; and (f) -J-R³ is an N-aryl substituted piperazinylgroup; (v) R¹ is other than hydroxy, alkoxy, aryloxy, alkyl or aryl whenconditions (g) and (h) are both met, or R¹ and R^(1a) do not form ═CH₂when conditions (g) and (h) are both met (g) R² is alkyl, aryl orarylalkyl; and (h) -J-R³ is —NR^(6e)R^(7e) or —(CHR²⁰)—R^(5c) whereR^(5c) is optionally substituted phenyl; R^(6e) is hydrogen, hydroxy oralkoxy; R^(7e) is optionally substituted phenyl; and R²⁰ is hydrogen,hydroxy or alkoxy; (vi) R² is other than optionally substituted phenylor pyridyl when conditions (j) and (k) are both met (j) R^(1a) is H,hydroxy, alkyl or (hydroxy)alkyl, and R¹ is H, hydroxy,—(CH₂)_(n)*—NR^(6f)R^(7f), —(CH₂)_(n)*—CO₂R^(8e), cycloalkyl,heterocylco, or heteroaryl; or R^(1a) and R¹ combine to form oxo,—O(CH₂)_(m)*O—, or ═CHCO₂R^(8e) where n* is 0 to 2; m* is 1 or 2; R^(6f)and R^(7f) are independently H, alkyl, alkenyl, (hydroxy)alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocylco,(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl,—C(O)-cycloalkyl, —C(O)-(cycloalkyl)alkyl, —C(O)-aryl,—C(O)-(aryl)alkyl, —C(O)-heterocylco, —C(O)-(heterocyclo)alkyl,—C(O)-alkyl-NR^(8e)R^(8f), —C(O)—NR^(8e)R^(8f), —CO₂-alkyl,-alkyl-CO₂-alkyl, —CO₂-cycloalkyl, —CO₂-(cycloalkyl)alkyl, —CO₂-aryl,—CO₂-(aryl)alkyl, —CO₂-heterocylco, —CO₂-(heterocylo)alkyl,—CO₂—NR^(8e)R^(8f), —CO₂-alkyl-NR^(8e)R^(8f), —NR^(8e)COR^(8f),-alkyl-NR^(8e)COR^(8f), —NR^(8e)CO₂R^(8f), -alkyl-NR^(8e)CO₂R^(8f),—C(O)N(R^(8e))(aryl), -alkyl-C(O)N(R^(8e))(aryl),—C(O)N(R^(8e))(heterocyclo), -alkyl-C(O)N(R^(8e))(heterocyclo); orR^(6f) and R^(7f) together with the nitrogen atome to which they areattached combine to form an optionally substituted heterocyclo ringselected from

R^(8e) and R^(8f) are independently H, alkyl, cycloalkyl, (fluoro)alkyl,or —CH₂CO₂-alkyl; R^(8g) is H, alkyl, cycloalkyl, (cycloalkyl)alkyl,aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl,(heteroaryl)alkyl, CHO, —C(O)-alkyl, —C(O)-cycloalkyl,—C(O)-(cycloalkyl)alkyl, —C(O)-aryl, —C(O)-(aryl)alkyl,—C(O)-heterocylco, —C(O)-(heterocyclo)alkyl, —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-(cycloalkyl)alkyl, —CO₂-aryl, —CO₂-(aryl)alkyl,—CO₂-hetercyclo, —CO₂-(heterocyclo)alkyl, —CO₂—NR^(6f)R^(7f), or—CO₂-(alkyl)-NR^(6f)R^(7f), (k) -J-R³ is a group—C(O)—NR^(8a1)—(CR¹⁵R¹⁶)—R^(5*), —(CR¹⁵R¹⁶)—NR^(8a1)—C(O)—R⁵*,—(CR¹⁵R¹⁶)—NR^(8a1)—(CR¹⁷R¹⁸)—R^(5*), —C(O)O—(CR¹⁵R¹⁶)—R^(5*),—(CR¹⁵R¹⁶)—OC(O)—R^(5*), —(CR¹⁵R¹⁶)—O—(CR¹⁷R¹⁸)—R^(5*),—(CR¹⁵)═C(R¹⁶)—R^(5*), —(CR¹⁵R¹⁶)—C(R¹⁷)═C(R¹⁸)—R^(5*),—(CR¹⁵R¹⁶)—C(R¹⁷R¹⁸)—(CR¹⁹R²⁰)—R^(5*), —C(O)—(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—R^(5*),—(CR¹⁵R¹⁶)—C(O)—(CR¹⁷R¹⁸)—R^(5*), —(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—C(O)—R^(5*),—N(R^(8a1))—C(O)—(CR¹⁵R¹⁶)—R^(5*),—N(R^(8a1))—(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—R^(5*), —N(R^(8a1))—C(O)—C(O)—R^(5*),—OC(O)—(CR¹⁵R¹⁶)—R^(5*), or —O—(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—R^(5*), where R^(5*)is

 where T^(1c)* is hydroxy, alkyl, fluoroalkyl, alkenyl, cycloalklyl,(cycloalkyl)alkyl, alkoxy, fluoroalkoxy, (alkoxy)alkyl, (alkoxy)alkoxy,(fluoroalkoxy)alkyl, alkenyloxy, cycloalkyloxy, (cycloalkyl)alkoxy,phenoxy, cyano, halo, —NT⁷T⁸ where T⁷ and T⁸ are as defined above, —SH,—ST⁶ where T⁶ is as defined above, —S(O)_(t)T⁶ where t is as definedabove, —C(O)_(t)H, —C(O)_(t)T⁶ or —C(O)—NT⁷T⁸; T^(2c)* is H, halogen,alkyl or alkoxy; or when T^(1c)* is adjacent to T^(2c)* they may combineto form a⁵ or⁶-membered heterocylo or heteroaryl ring optionallysubstituted with alkyl, fluroalkyl, ═O or ═S T^(3c)* is H, halogen,alkyl, fluroalkyl, alkoxy, fluoralkoxy, cycloalkyl, (cycloalkyl)alkyl,cyano, heteroaryl, —NT⁷T⁸, —SH, —ST⁶, —S(O)_(t)T⁶, —C(O)_(t)H,—C(O)_(t)T⁶ or —C(O)—NT⁷T⁸, or alkyl subsituted with cyano, CO₂H, CO₂T⁶,or —C(O)—NT⁷T⁸; and R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently H,hydroxy, alkyl, alkenyl, (hydroxy)alkyl, (alkoxy)alkyl,—(CH₂)_(n)*—NR^(6f)R^(7f), —CHO, —C(O)alkyl, or —CO₂alkyl; or R¹⁵ andR¹⁶ together form —CH₂CH₂—; or R¹⁷ and R¹⁸ together form —CH₂CH₂—; orR¹⁹ and R²⁰ together form —CH₂CH₂—; (vii) R^(8a4) is other than H orC₁₋₄-alkyl when conditions (l) to (t) are all met: (l) p is 2; (m) R¹and R^(1a) are H; (n) R² is C₁₋₁₀-alkyl, C₁₋₁₀-haloalkyl orC₁₋₈alkoxy-C₁₋₈-alkyl. (o) J is a bond; (p) R³ is —N(R^(8a1))—C(Z¹)-R⁵;(q) R^(8a1) is H or C₁₋₄-alkyl; (r) Z¹ is ═NR^(8a4); (s) R^(5a) is—NR^(6a)R^(7a); and (t) R^(6a) is H or C₁₋₄-alkyl; (viii) R^(1a) isother than H when conditions (u) to (qq) are met: (u) R¹ is

 —N(R⁸)C(O)R¹⁴, —SO₂R^(8c), —OC(O)CCl₃, —NR⁶R⁷, —OC(O)NR⁶R⁷, —N₃, nitro,or hydroxy; (v) R² is aryl, which may be optionally independentlysubstituted with one or more groups T¹, T² or T³; (w) J is a C₁₋₄alkylene optionally independently substituted with one or more groupsT^(1a), T^(2a) or T^(3a); (x) R³ is —R⁵; (y) R⁴ is alkyl, haloalkyl,alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which maybe optionally independently substituted with one or more groups T^(1b),T^(2b) or T^(3b); (z) R^(4a) is R⁴ or OR⁴; (aa) R⁵ is —NR^(6a)R^(7a);(bb) R⁶, R⁷, R⁸, R^(8a), R^(8a2), R^(8a4), and R^(8a5) are independentlyH, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,(heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R¹², —CO₂R¹²,—C(O)—NR¹²R¹³, or —NR¹²R¹³ any of which may be optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d); or R⁶ andR⁷, together with the nitrogen atom to which they are attached maycombine to form a saturated or unsaturated 4 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); or one of R⁶ or R⁷, may combine with one of R⁸ orR^(8a) to form a saturated or unsaturated 5 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2b) or T^(3d); (cc) R^(6a) is H; (dd) R^(7a) is heteroaryl, which maybe optionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); (ee) R^(8b) is independently H, alkyl, aryl, cyano,nitro, acyl or —SO₂(alkyl); (ff) R^(8c) is independently H, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl,heteroaryl, amino or alkoxy; (hh) R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴,CONR⁶R⁷, or SO₂—NR⁶R⁷; (ii) R¹² and R¹³ are independently H, alkyl,hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any ofwhich may be optionally independently substituted with one or moregroups T^(1f), T^(2f) or T^(3f) or R^(12 a) nd R¹³ together with thenitrogen atom to which they are attached may combine to form a saturatedor unsaturated ring which may be optionally independently substitutedwith one or more groups T^(1f), T^(2f) or T^(3f); (jj) W is ═NR^(8a2),═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or ═N—SO₂R^(8a2); (kk) Z and Z² areindependently ═O, ═S, ═NR^(8a4) or ═N—CN; (ll) R¹⁴ is independently

 where q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; (mm) X² is one or more optional substituents, attachedto any available ring carbon atom, independently selected from T^(1g),T^(2g)or T^(3g); (nn) T^(1-1g), T^(2-2g) or T^(3-3g) are eachindependently (1) hydrogen or T⁶, where T⁶ is (i) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,clycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i)which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more (preferably 1 to 3) of the following groups(2) to (13) of the definition of T^(1-1g), T^(2-2g) and T^(3-3g); (2)—OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶,where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶, (6) halo,(7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸, (10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11)-T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13) oxo, (oo) T⁴ and T⁵ areeach independently (1) a single bond, (2) -T¹¹-S(O)_(t)-T¹²-, (3)-T¹¹-C(O)-T¹²-, (4) -T¹¹-(S)-T¹²-, (5) -T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-, (7)-T¹¹-O—C(O)-T¹²-, (8) -T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-, or(10) -T¹¹-C(O)—C(O)-T¹²-, (pp) T⁷, T⁸, T⁹, T⁹ and T¹⁰ (1) are eachindependently hydrogen or a group provided in the definition of T⁶, or(2) T⁷ and T⁸ may together be alkylene or alkenylene, completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached, which ring is unsubstituted or substituted withone or more groups listed in the definition of T^(1-1g), T^(2-2g) andT^(3-3g), or (3) T⁷ or T⁸, together with T⁹, may be alkylene oralkenylene completing a 3- to 8-membered saturated or unsaturated ringtogether with the nitrogen atoms to which they are attached, which ringis unsubstituted or substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹and T¹⁰ together with the nitrogen atom to which they are attached maycombine to form a group —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are eachindependently H or a group provided in the definition of T⁶; (qq) T¹¹and T¹² are each independently (1) a single bond, (2) alkylene, (3)alkenylene, or (4) alkynylene.
 2. A compound of claim 1 wherein R¹ is

where R⁷ is heteroaryl.
 3. A compound of claim 1 wherein J is a bond oralkylene; R¹ is

H,  or hydroxy; R² is alkyl, benzyl, phenyl, thienyl, or benzothienylany of which may be optionally substituted with one or more groups T¹,T² or T³;

R⁵ is optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl or—NR^(6a)R^(7a).
 4. A compound of claim 1 wherein R^(1 is) (a)—N(R⁸)—SO₂—NR⁶R⁷, or —N(R⁸)—C(W)—NR⁶R⁷ where R⁶ and R⁷ are independently(i) H, or (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl,(heterocyclo)alkyl, or (alkoxy)alkyl, any of which may be optionallyindependently substituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶,NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl, or R⁶ and R⁷ combine to form aheterocylo ring optionally substituted with one or more OH, SH, OT⁶,ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl,heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl; and R⁸ is (i) H; or (ii) alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky,(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which maybe optionally independently substituted with one or more OH, SH, OT⁶,ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl,heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl, (b)—N(R⁸)-C(Z)—N(R^(8a))—SO₂—OH where R⁴ is (i) H, or (ii) alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxy,(aryl)alkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl or(alkoxy)alkyl, any of which may be optionally independently substitutedwith one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo,alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,(OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl,(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and R⁸ and R^(8a)are independently (i) H; or (ii) alkyl, cycloalkyl, aryl, heteroaryl,heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or(heterocyclo)alkyl, any of which may be optionally independentlysubstituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T₈, cyano,halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,(SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,(cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or(c) or a group

R^(1a) is H,; R² is phenyl, (phenyl)alkyl, napthyl, thienylbenzothienyl, alkyl or alkenyl any of which may be optionallyindependently substituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶,NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl; J is a bond, methylene orethylene; R³ is (a) —R⁵ where R⁵ is heteroaryl, heterocyclo or—NR^(6a)R^(7a), any of which may be optionally independently substitutedwith one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo,alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,(OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl,(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; (b) —C(Z¹)-R⁵ or—O—C(Z¹)-R⁵, where R⁵ is aryl, (aryl)alkyl, heteroaryl,(heteroaryl)alkyl) or —NR^(6a)R^(7a); and R^(6a) and R^(7a) areindependently (i) H; or (ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl,heteroaryl (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl, any ofwhich may be optionally independently substituted with one or more OH,SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl,aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl,(ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl; or (c) —N(R^(8a1))—C(Z¹)-R⁵, or—N(R^(8a1))—SO₂—R⁵ where R⁵ is aryl, (aryl)alkyl, hetreoaryl,(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, cycloalkyl,(alkoxy)alkyl, or (cycloalkoxy)alkyl, any of which may be optionallyindependently substituted with one or more OH, SH, OT , ST , C(O)_(t)T⁶,NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl; and R^(8a1) iS (i) H; or (ii)alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky,(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which maybe optionally independently substituted with one or more OH, SH, OT⁶,ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl,heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl, R⁵ is optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheteroayl, optionally substituted aryl or —NR^(6a)R^(7a); R⁶, R^(6a), R⁷and R^(7a) are independently H, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocyclo, optionally substituted (aryl)alkyl, optionallysubstituted (heteroaryl)alkyl, optionally substituted(heterocylco)alkyl, optionally substituted alkyl, or COR¹²; or R⁶ andR⁷, or R^(6a) and R^(7a) together with the nitrogen to which they areattached combine to form an optionally substituted saturated orunsaturated 5 to 8 membered ring.
 5. A compound of claim 1 wherein R¹ is(a) hydrogen, or hydroxy; (b) —O—C(O)—NR⁶R⁷, —N(R⁸)—SO₂—NR⁶R⁷, or—N(R⁸)—C(W)-NR⁶R⁷ where R⁶ and R⁷ are independently (i) H, or (ii)alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxy, (aryl)alkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl,(heterocyclo)alkyl, or (alkoxy)alkyl, any of which may be optionallyindependently substituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶,NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl,heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl, or R⁶ and R⁷ combine to form aheterocylo ring optionally substituted with one or more OH, SH, OT⁶,ST⁶, C(O)_(t)T⁶, NT⁷T⁷, cyano, halo, oxo, alkyl, haloalkyl, aryl,heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl; and R⁸ is (i) H; or (ii) alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky,(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which maybe optionally independently substituted with one or more OH, SH, OT⁶,ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl, aryl,heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl,(C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl, or (c) a group

R^(1a) is H; R² is phenyl, (phenyl)alkyl, napthyl, thienyl benzothienyl,alkyl or alkenyl, any of which may be optionally independentlysubstituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano,halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,(SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,(cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; J isa bond, methylene or ethylene; R³ is (a) —R⁵ where R⁵ is heteroaryl orheterocyclo, either of which may be optionally independently substitutedwith one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo,alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,(OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl,(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; (b) —C(Z¹)-R⁵, or—O—C(Z¹)-R⁵, where Z¹is ═NR^(8a4) or ═N—CN; R⁵ is aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl) or —NR^(6a)R^(7a); and R^(6a) and R^(7a)are independently (i) H; or (ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl,heteroaryl (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl, any ofwhich may be optionally independently substituted with one or more OH,SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano, halo, oxo, alkyl, haloalkyl,aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT⁶)alkyl,(ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl, (cyano)alkyl, (aryl)alkyl,(heteroaryl)alkyl or (heterocyclo)alkyl; or (c) —N(R^(8a1))—C(Z¹)-R⁵, or—N(R^(8a1))—SO₂—R⁵ where Z¹is ═NR^(8a4) or ═N—CN; R⁵ is aryl,(aryl)alkyl, hetreoaryl, (heteroaryl)alkyl, heterocyclo,(heterocyclo)alkyl, alkyl, cycloalkyl, (alkoxy)alkyl, or(cycloalkoxy)alkyl, any of which may be optionally independentlysubstituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano,halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,(SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,(cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; andR^(8a1) is (i) H; or (ii) alkyl, cycloalkyl, aryl, heteroaryl,heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or(heterocyclo)alkyl, any of which may be optionally independentlysubstituted with one or more OH, SH, OT⁶, ST⁶, C(O)_(t)T⁶, NT⁷T⁸, cyano,halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,(SH)alkyl, (OT⁶)alkyl, (ST⁶)alkyl, (C(O)_(t)T⁶)alkyl, (NT⁷T⁸)alkyl,(cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, R⁵is optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heteroayl, optionally substituted aryl or—NR^(6a)R^(7a); R⁶, R^(6a), R⁷ and R^(7a) are independently H,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substituted heterocyclo,optionally substituted (aryl)alkyl, optionally substituted(heteroaryl)alkyl, optionally substituted (heterocylco)alkyl, optionallysubstituted alkyl, or COR¹²; or R⁶ and R⁷, or R^(6a) and R^(7a) togetherwith the nitrogen to which they are attached combine to form anoptionally substituted saturated or unsaturated 5 to 8 membered ring. 6.A pharmaceutical composition comprising at least one compound of claim 1together with a suitable vehicle or carrier therefor.
 7. Apharmaceutical composition of claim 6 further comprising at least oneadditional therapeutic agent selected from anti-arrhythmic agents,calcium channel blockers, anti-platelet agents, anti-hypertensiveagents, anti-thrombotic/anti-thrombolytic agents, anti-coagulants,3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors,anti-diabetic agents, thyroid mimetics, mineralocorticoid receptorantagonists, or cardiac glycosides.
 8. The pharmaceutical composition ofclaim 7 wherein (a) the additional anti-arrhythmic agent is selectedfrom sotalol, dofetilide, diltiazem and verapamil; (b) the anti-plateletagent is selected from clopidogrel, ifetroban and aspirin; (c) theanti-hypertensive agent is selected from beta adrenergic blockers,angiotensin-converting enzyme inhibitors, angiotensin II antagonists,endothelin antagonists, Dual endothelin/angiotensin II antagonists, andvasopepsidase inhibitors; (d) the anti-thrombotic/anti-thrombolyticagent is selected from tissue plasminogen activator, recombinant tissueplasminogen activator, tenecteplase, lanoteplase, factor VIIainhibitors, factor Xa inhibitors and thrombin inhibitors; (e) theanti-coagulant is selected from warfarin and heparins; (f) the3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is selectedfrom pravastatin, lovastatin, atorvastatin, simvastatin, Itavastatin androsuvastatin; (g) the anti-diabetic agent is selected from biguanidesand biguanide/glyburide combinations; (h) the mineralocorticoid receptorantagonist is selected from spironolactone and eplerinone; and (i) thecardiac glycoside is selected from digitalis and ouabain.
 9. Thepharmaceutical composition of claim 8 wherein (a) theangiotensin-converting enzyme inhibitors are selected from captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, and lisinopril; and (b) thevasopepsidase inhibitors are selected from omapatrilat and gemopatrilat.10. A method treating I^(Kur)-associated disorders comprising the stepof administering to a patient in need thereof an effective amount of atleast one compound of the following formula I

enantiomers, diastereomers, solvates or salts thereof wherein m is 1; pis 1 or 2; R¹ is

 —CO₂H, —C(O)R^(8c), —NR⁶R⁷, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, halo,perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl; R^(1a) is H, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; or R¹ and R^(1a)together form oxo; or R¹ and R^(1a) together with the carbon atom towhich they are attached combine to form an optionally substitutedspiro-fused heterocyclo group; or R¹ and R_(ia) together combine to forma group

R² is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may beoptionally independently substituted with one or more groups T¹, T² orT³; J is a bond or C₁₋₄ alkylene optionally independently substitutedwith one or more groups T^(1a), T^(2a) or T^(3a); R³ is

R⁴ is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, orheteroaryl any of which may be optionally independently substituted withone or more groups T^(1b), T^(2b) or T^(3b); R^(4a) is R⁴ or OR⁴; R⁵ is—NR^(6a)R^(7a), or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl,alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or(heterocyclo)alkyl, any of which may be optionally independentlysubstituted with one or more groups T^(1c), T^(2c) or T^(3c); R⁶,R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8a1), R^(8a2), R^(8a3), R^(8a4),R^(8a5), and R⁹, are independently H, alkyl, hydroxy, alkoxy, aryloxy,heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl,(aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl,(cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl,heterocyclo, (heterocyclo)alkyl, —C(O)R¹², —CO₂R¹², or —C(O)—NR²KR¹³,any of which may be optionally independently substituted with one ormore groups T^(1d), T^(2d) or T^(3d); or R⁶ and R⁷, or R^(6a) andR^(7a)together with the nitrogen atom to which they are attached maycombine to form a saturated or unsaturated 4 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); or one of R⁶ or R⁷, may combine with one of R⁸, R^(8a)or R⁹ to form a saturated or unsaturated 5 to 8 membered ring optionallyindependently substituted with one or more groups T^(d), T^(2d) orT^(3d). or one of R^(6a) or R^(7a), may combine with R^(8a1) to form asaturated or unsaturated 5 to 8 membered ring optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d) R^(8b) isindependently H, alkyl aryl, cyano, nitro, acyl or —SO₂(alkyl); R^(8c)is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloheteroalkyl, heteroaryl, amino or alkoxy; R^(8d) is R⁴, COR⁴,CO₂R⁴, SO₂R⁴, CONR⁶R⁷, or SO₂—NR⁶R⁷; R¹⁰ R^(10a), R¹¹ and R^(11a) areindependently H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo,hydroxy, (hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl,heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl,(cycloalkyl)alkyl, or cyano any of which may be optionally independentlysubstituted on available atoms with one or more groups T^(1e), T^(2e) orT^(3e); or R¹⁰ and R^(10a) or R¹¹ and R^(11a) may combine to form oxo;or R^(10a) may combine with R^(11a) to form a bond; or R¹⁰ may combinewith R⁹ to form a saturated or unsaturated ring; R¹² and R¹³ areindependently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,(heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl,heterocyclo, or (heterocyclo)alkyl any of which may be optionallyindependently substituted with one or more groups T^(1f), T^(2f) orT^(3f) or R¹² and R¹³ together with the nitrogen atom to which they areattached may combine to form a saturated or unsaturated ring which maybe optionally independently substituted with one or more groups T^(1f),T^(2f) or T^(3f); W is ═NR^(8a2), ═N—CO^(8a2), ═N—COR^(8a2), ═N—CN, or═N—SO₂R^(8a2); X is

Z, Z¹ and Z² are independently ═O, ═S, ═NR^(8a4) or ═N—CN; R¹⁴ isindependently

 where q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; R^(X) is one or more optional substituents, attached toany available ring carbon atom, independently selected from T^(1g),T^(2g) or T^(3g); T^(1-1g), T^(2-2g) or T^(3-3g) are each independently(1) hydrogen or T⁶, where T⁶ is (i) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i)which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more (preferably 1 to 3) of the following groups(2) to (13) of the definition of T^(1-1g), T^(2-2g) or T^(3-3g); (2) —OHor —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶,where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶, (6) halo,(7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸, (10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11)-T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13) oxo, T⁴ and T⁵ are eachindependently (1) a single bond, (2) -T¹¹-S(O)_(t)-T¹²-, (3)-T¹¹-C(O)-T¹²-, (4) -T¹¹-C(S)-T¹²-, (5) -T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-,(7) -T¹¹-O—C(O)-T¹²-, (8) -T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-,or (10) -T¹¹-C(O)—C(O)-T¹²- , T⁷, T⁸, T⁹, T⁹, T^(9a) and T¹⁰ (1) areeach independently hydrogen or a group provided in the definition of T⁶,or (2) T⁷ and T⁸may together be alkylene or alkenylene, completing a 3-to 8 -membered saturated or unsaturated ring together with the atoms towhich they are attached, which ring is unsubstituted or substituted withone or more groups listed in the definition of T^(1-1g)g, T^(2-2g)andT^(3-3g), or (3) T⁷ or T⁸, together with T⁹, may be alkylene oralkenylene completing a 3- to 8 -membered saturated or unsaturated ringtogether with the nitrogen atoms to which they are attached, which ringis unsubstituted or substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸or T⁹ andT¹⁰ together with the nitrogen atom to which they are attached maycombine to form a group —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are eachindependently H or a group provided in the definition of T⁶; T¹¹ and T¹²are each independently (1) a single bond, (2) alkylene, (3) alkenylene,or (4) alkynylene; provided that: (i) R² is other than

 when conditions (a) and (b) are both met (a) -J-R³ is

(b) R¹ is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy,heteroaryloxy, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, —OC(═O)CCl₃, —SO₂(alkyl),—SO²(aryl), —SO²(arylalkyl), —CO₂H, —C(═O)(alkyl), —CO₂(alkyl),—C(═O)NR^(6*)R^(7*), —NR^(6*)R^(7*), —OC(═O)NR^(6*)R^(7*), —N₃,—N(R⁸)C(O)NR^(6*)R^(7*), —OC(═O)OR⁴—OC(═O)R⁴, or —N(H)S(O₂)R⁴, or R¹ andR^(1a) combine to form oxo; or R¹ and R^(1a) together with the carbonatom to which they are attached combine to form a spiro fusedheterocyclo group, or R¹ and R^(1a) together combine to form a group

 where R^(6*) and R^(7*) are each independently H, aryl, —C(O)aryl,—CO₂aryl, alkyl, —C(O)alkyl, —CO₂alkyl, —S(O)_(u)alkyl,—C(O)S(O)_(u)alkyl, —S(O)_(u)aryl, —C(O)S(O)_(u)aryl, or heterocyclo;R^(5a) is

R^(8a) H, or alkyl; and u is 0, 1, 2 or 3; (ii) R^(1a) is other than Hwhen conditions (c) to (x) are met: (c) R¹ is

 —N(R⁸)C(O)R¹⁴, —SO₂R^(8c), —OC(O)CCl₃, —NR⁶R⁷, —OC(O)NR⁶R⁷, —N₃, nitro,or hydroxy; (d) R² is aryl, which may be optionally independentlysubstituted with one or more groups T¹, T²or T³; (e) J is a C₁₋₄alkylene optionally independently substituted with one or more groupsT^(1a), T^(2a) or T^(3a); (f) R³ is —R ; (g) R⁴ is alkyl, haloalkyl,alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which maybe optionally independently substituted with one or more groups T^(1b),T^(2b) or T^(3b); (h) R^(4a) is R⁴or OR⁴; (i) R⁵is—NR^(6a)R^(7a); (j)R⁶, R⁷, R⁸, R^(8a), R^(8a2), R^(8a4), and R^(8a5) are independently H,alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,(heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R¹², —CO₂R¹²—C(O)—NR¹²R¹³, or —NR¹²R¹³ any of which may be optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d); or R⁶ andR⁷, together with the nitrogen atom to which they are attached maycombine to form a saturated or unsaturated 4 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2d) or or T^(3d); or one of R⁶ or R⁷, may combine with one of Rs or Ra to form a saturated or unsaturated 5 to 8 membered ring optionallyindependently substituted with one or more groups T^(1d), T^(2d) orT^(3d). (k) R^(6a) is H; (l) R^(7a) is heteroaryl, which may beoptionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); (m) R^(8b) is independently H, alkyl, aryl, cyano,nitro, acyl or —SO₂(alkyl); (n) R^(8c) is independently H, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl,heteroaryl, amino or alkoxy; (O) R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴,CONR⁶R⁷, or SO₂—NR⁶R⁷; (p) R¹² and R¹³ are independently H, alkyl,hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any ofwhich may be optionally independently substituted with one or moregroups T^(1f), T^(2f) or T^(3f) or R¹² and R¹³ together with thenitrogen atom to which they are attached may combine to form a saturatedor unsaturated ring which may be optionally independently substitutedwith one or more groups Tif, T^(2f) or T^(3f). (q) W is ═NR^(8a2),═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or ═N—SO₂R^(8a2); (r) Z and Z² areindependently ═O, ═S, ═NR^(8a4) or ═N—CN; (s) R¹⁴ is independently

 where q is 1, 2 or 3; K^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; (t) K^(X) is one or more optional substituents,attached to any available ring carbon atom, independently selected fromT^(1g), T^(2g) or T^(3g); (u) T^(1-1g), T^(2-2g), and T^(3-3g) are areeach independently (1) hydrogen or T⁶, where T⁶ is (i) alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii)a group (i) which is itself substituted by one or more of the same ordifferent groups (i); or (iii) a group (i) or (ii) which isindependently substituted by one or more (preferably I to³) of thefollowing groups (2) to (13) of the definition of T^(1-1g), T^(2-2g) andT^(3-3g), (2) —OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶,or —O—C(O)T⁶, where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, orS(O)_(t)N(T⁹)T⁶, (6) halo, (7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸ (10)-T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11) -T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13)oxo, T⁴ and T⁵ are each independently (1) a single bond, (2)-T¹¹-S(O)_(t)-T¹², (3) -T¹¹-C(O)-T¹², (4) -T¹¹-C(S)-T¹², (5)-T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-, (7) -T¹¹-O—C(O)-T¹²-, (8)-T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-, or (10) -T¹¹-C(O)—C(O)-T¹²-(w) T⁷, T⁸, T⁹, T^(9a) and T¹⁰ (1) are each independently hydrogen or agroup provided in the definition of T⁶, or (2) T⁷ and T⁸ may together bealkylene or alkenylene, completing a 3- to 8-membered saturated orunsaturated ring together with the atoms to which they are attached,which ring is unsubstituted or substituted with one or more groupslisted in the description of T^(1-1g), T^(2-2g) and T^(3-3g), or (3) T⁷or T⁸, together with T⁹, may be alkylene or alkenylene completing a 3-to 8-membered saturated or unsaturated ring together with the nitrogenatoms to which they are attached, which ring is unsubstituted orsubstituted with one or more groups listed in the description ofT^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹ and T¹⁰ togetherwith the nitrogen atom to which they are attached may combine to form agroup —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are each independently H or a groupprovided in the definition of T⁶; (x) T¹¹ and T¹² are each independently(1) a single bond, (2) alkylene, (3) alkenylene, or (4) alkynylene. 11.The method of claim 10 wherein the I^(Kur)-associated condition isarrhythmia, a gastrointestinal disorder or an inflammatory orimmunological disease.
 12. The method of claim 11 wherein the arrhythmiais a supraventricular arrhythmia.
 13. The method of claim 12 wherein thesupraventricular arrhythmia is atrial fibrillation or atrial flutter.14. The method of claim 11 wherein the gastrointestinal disorder isreflux esauphagitis or a motility disorder.
 15. The method of claim 11wherein the inflammatory disease is chronic obstructive pulmonarydisease.
 16. A method of treating diabetes, cognitive disorders, orepilepsy comprising administering to a patient in need thereof aneffective amount of at least one compound of the following formula I

enantiomers, diastereomers, solvates or salts thereof wherein m is 1; pis 1 or 2; R¹ is

 —CO₂H, —C(O)R^(8c), —NR⁶R⁷, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, halo,perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl; R^(1a) is H, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; or R¹ and R^(1a)together form oxo; or R¹ and R^(1a) together with the carbon atom towhich they are attached combine to form an optionally substitutedspiro-fused heterocyclo group; or R¹ and R^(1a) together combine to forma group

 R² is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may beoptionally independently substituted with one or more groups T¹, T² orT^(3;) J is a bond or C₁₋₄ alkylene optionally independently substitutedwith one or more groups T^(1a), T^(2a) or T^(3a); R³ is

R⁴ is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, orheteroaryl any of which may be optionally independently substituted withone or more groups T^(1b), T^(2b) or T^(3b); R^(4a) is R⁴ or OR⁴; R⁵ is—NR^(6a)R^(7a), or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl,alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or (heterocyclo)alkyl,any of which may be optionally independently substituted with one ormore groups T^(1c), T^(2c) or T^(3c); R⁶, R^(6a), R⁷, R^(7a), R⁸,R^(8a), R^(8a1), R^(8a2), R^(8a3), R^(8a4), R^(8a5) and R⁹ areindependently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,(heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl,(alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo,(heterocyclo)alkyl, —C(O)R¹², —CO₂R¹², or —C(O)—NR¹²R¹³, any of whichmay be optionally independently substituted with one or more groupsT^(1d) T^(2d) or T^(3d); or R⁶ and R⁷, or R^(6a) and R^(7a) togetherwith the nitrogen atom to which they are attached may combine to form asaturated or unsaturated 4 to 8 membered ring optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d); or one ofR⁶ or R⁷, may combine with one of R⁸, R^(8a) or R⁹ to form a saturatedor unsaturated 5 to 8 membered ring optionally independently substitutedwith one or more groups T^(1d), T^(2d) or T^(3d). or one of R^(6a) orR^(7a), may combine with R^(8a1) to form a saturated or unsaturated 5 to8 membered ring optionally independently substituted with one or moregroups T^(1d), T^(2d) or T^(3d) R^(8b) is independently H, alkyl, aryl,cyano, nitro, acyl or —SO₂(alkyl); R^(8c) is independently alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl,heteroaryl, amino or alkoxy; R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴, CONR⁶R⁷,or SO₂—NR⁶R⁷; R¹⁰R^(10a), R¹¹ and R^(11a) are independently H, alkyl,aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl,amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo,(heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or cyanoany of which may be optionally independently substituted on availableatoms with one or more groups T^(1e), T^(2e) or T^(3e); or R¹⁰ andR^(10a), or R¹¹ and R^(11a) may combine to form oxo; or R^(10a) maycombine with R^(11a) to form a bond; or R¹⁰ may combine with R⁹ to forma saturated or unsaturated ring; R¹² and R¹³ are independently H, alkyl,hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,(alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any ofwhich may be optionally independently substituted with one or moregroups T^(1f), T^(2f) or T^(3f) or R¹² and R¹³ together with thenitrogen atom to which they are attached may combine to form a saturatedor unsaturated ring which may be optionally independently substitutedwith one or more groups T^(1f), T^(2f) or T^(3f); W is ═NR^(8a2),═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or ═N—SO₂R^(8a2); X is

Z, Z¹ and Z² are independently ═O, ═S, ═NR^(8a4) or ═N—CN; R¹⁴ isindependently

 where q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; R^(X) is one or more optional substituents, attached toany available ring carbon atom, independently selected from T^(1g),T^(2g) or T^(3g); T^(1-1g), T^(2-2g), and T^(3-3g) are eachindependently (1) hydrogen or T⁶, where T⁶ is (i) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i)which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more (preferably 1 to 3) of the following groups(2) to (13) of the definition of T^(1-1g), T^(2-2g) and T^(3-3g), (2)—OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶,where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶, (6) halo,(7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸, (10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11)-T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13) oxo, T⁴ and T⁵ are eachindependently (1) a single bond, (2) -T¹¹-S(O)_(t)-T¹²-, (3)-T¹¹-C(O)-T¹²-, (4) -T¹¹-C(S)-T¹²-, (5) -T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-,(7) -T¹¹-O—C(O)-T¹²-, (8) -T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-,or (10) -T¹¹-C(O)—C(O)-T¹²- T⁷, T⁸, T⁹, T^(9a) and T¹⁰ (1) are eachindependently hydrogen or a group provided in the definition of T⁶, or(2) T⁷ and T⁸ may together be alkylene or alkenylene, completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached, which ring is unsubstituted or substituted withone or more groups listed in the definition of T^(1-1g), T^(2-2g) andT^(3-3g), or (3) T⁷ or T⁸, together with T⁹, may be alkylene oralkenylene completing a 3- to 8-membered saturated or unsaturated ringtogether with the nitrogen atoms to which they are attached, which ringis unsubstituted or substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹and T¹⁰ together with the nitrogen atom to which they are attached maycombine to form a group —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are eachindependently H or a group provided in the definition of T⁶; T¹¹ and T¹²are each independently (1) a single bond, (2) alkylene, (3) alkenylene,or (4) alkynylene; provided that: (i) R² is other than

 when conditions (a) and (b) are both met (a) -J-R³ is

 (b) R¹ is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy,heteroaryloxy, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, —OC(═O)CCl₃, —SO₂(alkyl),—SO₂(aryl), —SO₂(arylalkyl), —CO₂H, —C(═O)(alkyl), —CO₂(alkyl),—C(═O)NR^(6*)R^(7*), —NR^(6*)R^(7*), —OC(═O)NR^(6*)R^(7*), —N₃,—N(R⁸)C(O)NR^(6*)R^(7*), —OC(═O)OR⁴—OC(═O)R⁴, or —N(H)S(O₂)R⁴, or R¹ andR^(1a) combine to form oxo; or R¹ and R^(1a) together with the carbonatom to which they are attached combine to form a spiro fusedheterocyclo group, or R¹ and R^(1a) together combine to form a group

 where R^(6*) and R^(7*) are each independently H, aryl, —C(O)aryl,—CO₂aryl, alkyl, —C(O)alkyl, —CO₂alkyl, —S(O)_(u)alkyl,—C(O)S(O)_(u)alkyl, —S(O)_(u)aryl, —C(O)S(O)_(u)aryl, or heterocyclo;R^(5a) is

 R^(8a)H, or alkyl; and u is 0, 1, 2 or 3; (ii) R^(1a) is other than Hwhen conditions (c) to (x) are met: (c) R¹ is

 —N(R⁸)C(O)R¹⁴, —SO₂R^(8c), —OC(O)CCl₃, —NR⁶R⁷, —OC(O)NR⁶R⁷, —N₃, nitro,or hydroxy; (d) R² is aryl, which may be optionally independentlysubstituted with one or more groups T¹, T² or T³; (e) J is a C₁₋₄alkylene optionally independently substituted with one or more groupsT^(1a), T^(2a) or T^(3a); (f) R³ is —R⁵; (g) R⁴ is alkyl, haloalkyl,alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which maybe optionally independently substituted with one or more groups T^(1b),T^(2b) or T^(3b); (h) R^(4a) is R⁴or OR⁴; (i) R⁵ is —NR^(6a)R^(7a); (j)R⁶, R⁷, R⁸, R^(8a), R^(8a2), R^(8a4), and R^(8a5) are independently H,alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,(heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R¹², —CO₂R¹²,—C(O)—NR¹²R¹³, or —NR¹²R¹³ any of which may be optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d); or R⁶ andR⁷, together with the nitrogen atom to which they are attached maycombine to form a saturated or unsaturated 4 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); or one of R⁶ or R⁷, may combine with one of R⁸ orR^(8a) to form a saturated or unsaturated 5 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d). (k) R^(6a) is H; (l) R^(7a) is heteroaryl, which maybe optionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); (m) R^(8b) is independently H, alkyl, aryl, cyano,nitro, acyl or —SO₂(alkyl); (n) R^(8c) is independently H, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl,heteroaryl, amino or alkoxy; (o) R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴,CONR⁶R⁷, or SO₂—NR⁶R⁷; (p) R¹² and R¹³ are independently H, alkyl,hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any ofwhich may be optionally independently substituted with one or moregroups T^(1f), T^(2f) or T^(3f) or R¹² and R¹³ together with thenitrogen atom to which they are attached may combine to form a saturatedor unsaturated ring which may be optionally independently substitutedwith one or more groups T^(1f), T^(2f) or T^(3f); (q) W is ═NR^(8a2),═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or ═N—SO₂R^(8a2); (r) Z and Z² areindependently ═O, ═S, ═NR^(8a4) or ═N—CN; (s) R¹⁴ is independently

 where q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; (t) R^(X) is one or more optional substituents,attached to any available ring carbon atom, independently selected fromT^(1g), T^(2g) or T^(3g); (u) T^(1-1g), T^(2-2g), and T^(3-3g) are areeach independently (1) hydrogen or T⁶, where T⁶ is (i) alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii)a group (i) which is itself substituted by one or more of the same ordifferent groups (i); or (iii) a group (i) or (ii) which isindependently substituted by one or more (preferably 1 to 3) of thefollowing groups (2) to (13) of the definition of T^(1-1g), T^(2-2g) andT^(3-3g), (2) —OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶,or —O—C(O)T⁶, where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, orS(O)_(t)N(T⁹)T⁶, (6) halo, (7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸, (10)-T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11) -T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13)oxo, (v) T⁴ and T⁵ are each independently (1) a single bond, (2)-T¹¹-S(O)_(t)-T¹²-, (3) -T¹¹-C(O)-T¹²-, (4) -T¹¹-C(S)-T¹²-, (5)-T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-, (7) -T¹¹-O—C(O)-T¹² -, (8)-T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-, or (10) -T¹¹-C(O)—C(O)-T¹²-(w)T⁷, T⁸, T⁹, T^(9a) and T¹⁰ (1) are each independently hydrogen or agroup provided in the definition of T⁶, or (2) T⁷ and T⁸ may together bealkylene or alkenylene, completing a 3- to 8-membered saturated orunsaturated ring together with the atoms to which they are attached,which ring is unsubstituted or substituted with one or more groupslisted in the definition of T^(1-1g), T^(2-2g) and T^(3-3g), or (3) T⁷or T⁸, together with T⁹, may be alkylene or alkenylene completing a 3-to 8-membered saturated or unsaturated ring together with the nitrogenatoms to which they are attached, which ring is unsubstituted orsubstituted with one or more groups listed in the definition ofT^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹ and T¹⁰ togetherwith the nitrogen atom to which they are attached may combine to form agroup —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are each independently H or a groupprovided in the definition of T⁶; (x) T¹¹ and T¹² are each independently(1) a single bond, (2) alkylene, (3) alkenylene, or (4) alkynylene. 17.A compound of Formula I

enantiomers, diastereomers or salts thereof wherein m is 1; p is 1 or 2;R¹ is

 —NR⁶R⁷, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclo, halo, perfluoroalkyl, cyano, nitro,hydroxy, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted alkyl,optionally substituted alkenyl, or optionally substituted alkynyl;R^(1a) is H, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl; or R¹ and R^(1a) together form oxo; or R¹ and R^(1a)together with the carbon atom to which they are attached combine to forman optionally substituted spiro-fused heterocyclo group; or R¹ andR^(1a) together combine to form a group

 R² is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be optionallyindependently substituted with one or more groups T¹, T² or T³; J is abond or C₁₋₄ alkylene optionally independently substituted with one ormore groups T^(1a), T^(2a) or T^(3a); R³ is

 R⁴ is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, orheteroaryl any of which may be optionally independently substituted withone or more groups T^(1b), T^(2b) or T^(3b); R^(4a) is R⁴ or OR⁴; R⁵ is—NR^(6a) R^(7a), or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl,alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or(heterocyclo)alkyl, any of which may be optionally independentlysubstituted with one or more groups T^(1c), T^(2c) or T³; R⁶, R^(6a),R⁷, R^(7a), R⁸, R^(8a), R^(8a1), R^(8a2), R^(8a3), R^(8a4), R^(8a5), andR⁹ are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,(heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl,(alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo,(heterocyclo)alkyl, —C(O)R¹², —CO₂R¹², or —C(O)—NR¹²R¹³, any of whichmay be optionally independently substituted with one or more groupsT^(1d), T^(2d) or T^(3d); or R⁶ and R⁷, or R^(6a) and R^(7a) togetherwith the nitrogen atom to which they are attached may combine to form asaturated or unsaturated 4 to 8 membered ring optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d); or one ofR⁶ or R⁷, may combine with one of R⁸, R^(8a) or R⁹ to form a saturatedor unsaturated 5 to 8 membered ring optionally independently substitutedwith one or more groups T^(1d), T^(2d) or T^(3d). or one of R^(6a) orR^(7a), may combine with R^(8a1) to form a saturated or unsaturated 5 to8 membered ring optionally independently substituted with one or moregroups T^(1d), T^(2d) or T^(3d) R^(8b) is independently H, alkyl, aryl,cyano, nitro, acyl or —SO₂(alkyl); R^(8c) is independently alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl,heteroaryl, amino or alkoxy; R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴, CONR⁶R⁷,or SO₂—NR⁶R⁷; R¹⁰R^(10a), R^(11a) are independently H, alkyl, aryl,(aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl,amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo,(heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, cyano oroxo any of which may be optionally independently substituted onavailable atoms with one or more groups T^(1e), T^(2e) or T^(3e); orR^(10a) may combine with R^(11a) to form a bond; or R¹⁰ may combine withR⁹ to form a saturated or unsaturated ring; R¹² and R¹³ areindependently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,(heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl,heterocyclo, or (heterocyclo)alkyl any of which may be optionallyindependently substituted with one or more groups T^(1f), T^(2f) orT^(3f) or R¹² and R¹³ together with the nitrogen atom to which they areattached may combine to form a saturated or unsaturated ring which maybe optionally independently substituted with one or more groups T^(1f),T^(2f) or T^(3f); W is ═NR^(8a2), ═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or═N—SO₂R^(8a2); X is

 Z, Z¹ and Z² are independently ═O, ═S, ═NR^(8a4) or ═N—CN; R¹⁴ isindependently

 here q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂;R^(X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T)^(1g), T^(2g) or T^(3g); T^(1-1g), T^(2-2g), and T^(3-3g) are eachindependently (1) hydrogen or T⁶, where T⁶ is (i) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i)which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more (preferably 1 to 3) of the following groups(2) to (13) of the definition of T^(1-1g), T^(2-2g) and T^(3-3g), (2)—OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶,where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶, (6) halo,(7) cyano, (8) nitro, (9) -T⁴—NT⁷T⁸, (10) -T⁴—N(T⁹)-T⁵—NT⁷T⁸, (11)-T⁴—N(T¹⁰)-T⁵-T⁶, (12) -T⁴—N(T¹⁰)-T⁵—H, (13) oxo, T⁴ and T⁵ are eachindependently (1) a single bond, (2) -T¹¹—S(O)_(t)-T¹²-, (3)-T¹¹-C(O)-T¹²-, (4) -T¹¹-C(S)-T¹²-, (5) -T¹¹—O-T¹²-, (6) -T¹¹—S-T¹²-,(7) -T¹¹—O—C(O)-T¹²-, (8) -T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-,or (10) -T¹¹-C(O)—C(O)-T¹²- T⁷, T⁸, T⁹, T^(9a) and T¹⁰ (1) are eachindependently hydrogen or a group provided in the definition of T⁶, or(2) T⁷ and T⁸ may together be alkylene or alkenylene, completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached, which ring is unsubstituted or substituted withone or more groups listed in the definition of T^(1-1g), T^(2-2g) andT^(3-3g), or (3) T⁷ or T⁸, together with T⁹, may be alkylene oralkenylene completing a 3- to 8-membered saturated or unsaturated ringtogether with the nitrogen atoms to which they are attached, which ringis unsubstituted or substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹and T¹⁰ together with the nitrogen atom to which they are attached maycombine to form a group —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are eachindependently H or a group provided in the definition of T⁶; T¹¹ and T¹²are each independently (1) a single bond, (2) alkylene, (3) alkenylene,or (4) alkynylene; provided that (i) R² is other than

 when conditions (a) and (b) are both met (a) -J-R³ is

 and (b) R¹ is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy,heteroaryloxy, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, —OC(═O)CCl₃, —SO₂(alkyl),—SO₂(aryl), —SO₂(arylalkyl), —CO₂H, —C(═O)(alkyl), —CO₂(alkyl),—C(═O)NR^(6*)R^(7*), —NR^(6*)R^(7*), —OC(═O)NR^(6*)R^(7*), —N₃,—N(R⁸)C(O)NR^(6*)R^(7*), —OC(═O)OR⁴ —OC(═O)R⁴, or —N(H)S(O₂)R⁴, or R¹and R^(1a) combine to form oxo; or R¹ and R^(1a) together with thecarbon atom to which they are attached combine to form a spiro fusedheterocyclo group, or R¹ and R^(1a) together combine to form a group

 where R^(6*) and R^(7*) are each independently H, aryl, —C(O)aryl,—CO₂aryl, alkyl, —C(O)alkyl, —CO₂alkyl, —S(O)_(u)alkyl,—C(O)S(O)_(u)alkyl, —S(O)_(u)aryl, —C(O)S(O)_(u)aryl, or heterocyclo;R^(5a) is

 R^(8a) H, or alkyl; and u is 0, 1, 2 or 3; (ii) R² is other thanthienyl when conditions (c) and (d) are both met (c) -J-R³ is—NR^(6b)R^(7b) where R^(6b) and R^(7b) are independently H, alkyl,cycloalkyl, or R^(6b) and R^(7b) combine to form an N-containing cyclicgroup containing at least one double bond; and (d) R¹ is alkyl,cycloalkyl, alkenyl, alkynyl, alkoxy, amino or cyano (iii) said compoundis other than a compound of the formula

 where R^(1c) is —OC(O)NHR^(7c) or —OC(O)R^(4b;) R^(2a) is alkyl orphenyl;

 R^(4b) is alkyl; R^(5b) is —NHR^(7d) or benzyl substituted with one tothree groups independently selected from halo, alkyl or alkoxy R^(7c) isH, alkyl, phenyl or benzyl; R^(7d) is phenyl substituted with one tothree groups independently selected from halo, alkyl or alkoxy; R^(Xa)is hydroxy, —OC(O)NHR^(7c) or —OC(O)R^(4b); R^(Xb) and R^(Xc) areindependently H or alkyl; n^(*) is 1 to 4; n^(**) is 0 to 3; (iv) R² isother than phenyl when conditions (e) and (f) are both met (e) R¹ isalkyl, alkoxy, or phenyl; and (f) -J-R³ is an N-aryl substitutedpiperazinyl group; (v) R¹ is other than hydroxy, alkoxy, aryloxy, alkylor aryl when conditions (g) and (h) are both met, or R¹ and R^(1a) donot form ═CH₂ when conditions (g) and (h) are both met (g) R² is alkyl,aryl or arylalkyl; and (h) -J-R³ is —NR^(6e)R^(7e) or —(CHR²⁰)-R^(5c)where R^(5c) is optionally substituted phenyl; R^(6e) is hydrogen,hydroxy or alkoxy; R^(7e) is optionally substituted phenyl; and R²⁰ ishydrogen, hydroxy or alkoxy; (vi) R² is other than optionallysubstituted phenyl or pyridyl when conditions (j) and (k) are both met(j) R^(1a) is H, hydroxy, alkyl or (hydroxy)alkyl, and R¹ is H, hydroxy,—(CH₂)_(n)*-NR^(6f)R^(7f), —(CH₂)_(n)*—CO₂R^(8e), cycloalkyl,heterocyclo, or heteroaryl; or R^(1a) and R¹ combine to form oxo,—O(CH₂)_(m)*O—, or ═CHCO₂R^(8e where) n^(*) is 0 to 2; m^(*) is 1 or 2;R^(6f) and R^(7f) are independently H, alkyl, alkenyl, (hydroxy)alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl,—C(O)-cycloalkyl, —C(O)-(cycloalkyl)alkyl, —C(O)-aryl,—C(O)-(aryl)alkyl, —C(O)-heterocyclo, —C(O)-(heterocyclo)alkyl,—C(O)-alkyl-NR^(8e)R^(8f), —C(O)—NR^(8e)R^(8f), —CO₂-alkyl,-alkyl—CO₂-alkyl, —CO₂-cycloalkyl, —CO₂-(cycloalkyl)alkyl, —CO₂-aryl,—CO₂-(aryl)alkyl, —CO₂-heterocylco, —CO₂-(heterocyclo)alkyl,—CO₂—NR^(8e)R^(8f), —CO₂-alkyl—NR^(8e)R^(8f), —NR^(8e)COR^(8f),-alkyl—NR^(8e)COR^(8f), —NR^(8e)CO₂R^(8f), -alkyl—NR^(8e)CO₂R^(8f),—C(O)N(R^(8e))(aryl), -alkyl—C(O)N(R^(8e))(aryl),—C(O)N(R^(8e))(heterocyclo), -alkyl—C(O)N(R^(8e))(heterocyclo); orR^(6f) and R^(7f) together with the nitrogen atom to which they areattached combine to form an optionally substituted heterocyclo ringselected from

 R^(8e) and R^(8f) are independently H, alkyl, cycloalkyl,(fluoro)alkyl, or —CH₂CO₂-alkyl; R^(8g) is H, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl, —C(O)-cycloalkyl,—C(O)-(cycloalkyl)alkyl, —C(O)-aryl, —C(O)-(aryl)alkyl,—C(O)-heterocyclo, —C(O)-(heterocyclo)alkyl, —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-(cycloalkyl)alkyl, —CO₂-aryl, —CO₂-(aryl)alkyl,—CO₂-hetercyclo, —CO₂-(heterocyclo)alkyl, —CO₂—NR^(6f)R^(7f), or—CO₂-(alkyl)—NR^(6f)R^(7f); (k) -J-R³ is a group—C(O)—NR^(8a1)—(CR¹⁵R¹⁶)—R^(5*), —(CR¹⁵R¹⁶)—NR^(8a1)—C(O)—R^(5*),—(CR¹⁵R¹⁶)—NR^(8a1)—(CR¹⁷R¹⁸)—R^(5*), —C(O)O—(CR¹⁵R¹⁶)—R^(5*),—(CR¹⁵R¹⁶)—OC(O)—R^(5*), —(CR¹⁵R¹⁶)—O—(CR¹⁷R¹⁸)—R^(5*),—(CR¹⁵)═C(R¹⁶)—R^(5*), —(CR¹⁵R¹⁶)—C(R¹⁷)═C(R¹⁸)—R^(5*),—(CR¹⁵R¹⁶)—C(R¹⁷R¹⁸)—(CR¹⁹R²⁰)—R^(5*), —C(O)—(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—R^(5*),—(CR¹⁵R¹⁶)—C(O)—(CR¹⁷R¹⁸)—R^(5*), —(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—C(O)—R^(5*),—N(R^(8a1))—C(O)—(CR¹⁵R¹⁶)—R^(5*),—N(R^(8a1))—(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—R^(5*), —N(R^(8a1))—C(O)—C(O)—R^(5*),—OC(O)—(CR¹⁵R¹⁶)—R^(5*),or —O—(CR¹⁵R¹⁶)—(CR¹⁷R¹⁸)—R^(5*), where R^(5*)is

where T^(1c)* is hydroxy, alkyl, fluoroalkyl, alkenyl, cycloalklyl,(cycloalkyl)alkyl, alkoxy, fluoroalkoxy, (alkoxy)alkyl, (alkoxy)alkoxy,(fluoroalkoxy)alkyl, alkenyloxy, cycloalkyloxy, (cycloalkyl)alkoxy,phenoxy, cyano, halo, -NT⁷T⁸ where T⁷ and T⁸ are as defined above, —SH,—ST⁶ where T⁶ is as defined above, —S(O)_(t)T⁶ where t is as definedabove, —C(O)_(t)H, —C(O)_(t)T⁶ or —C(O)-NT⁷T⁸; T^(2c)* is H, halogen,alkyl or alkoxy; or when T^(1c)* is adjacent to T^(2c)* they may combineto form a⁵ or⁶-membered heterocylo or heteroaryl ring optionallysubstituted with alkyl, fluroalkyl, ═O or ═S T^(3c)* is H, halogen,alkyl, fluroalkyl, alkoxy, fluoralkoxy, cycloalkyl, (cycloalkyl)alkyl,cyano, heteroaiyl, -NT⁷T⁸, —SH, —ST⁶, —S(O)_(t)T⁶, —C(O)_(t)H,—C(O)_(t)T⁶ or —C(O)-NT⁷T⁸, or alkyl subsituted with cyano, CO₂H, CO₂T⁶,or —C(O)-NT⁷T⁸; and R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently H,hydroxy, alkyl, alkenyl, (hydroxy)alkyl, (alkoxy)alkyl,—(CH₂)_(n)*—NR^(6f)R^(7f), —CHO, —C(O)alkyl, or —CO₂alkyl; or R¹⁵ andR¹⁶ together form —CH₂CH₂—; or R¹⁷ and R¹⁸ together form —CH₂CH₂—; orR¹⁹ and R²⁰ together form —CH₂CH₂—; (vii) R^(1a) is other than H whenconditions (l) to (jj) are met: (l) R¹ is

 —N(R⁸)C(O)R¹⁴, —SO₂R^(8c), —OC(O)CCl₃, —NR⁶R⁷, —OC(O)NR⁶R⁷, —N₃, nitro,or hydroxy; (m) R² is aryl, which may be optionally independentlysubstituted with one or more groups T¹, T² or T³; (n) J is a C₁₋₄alkylene optionally independently substituted with one or more groupsT^(1a), T^(2a) or T^(3a); (o) R³ is —R⁵; (p) R⁴ is alkyl, haloalkyl,alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which maybe optionally independently substituted with one or more groups T^(1b),T^(2b) or T^(3b); (q) R^(4a) is R⁴ or OR⁴; (r) R⁵ is —NR^(6a)R^(7a); (s)R⁶, R⁷, R⁸, R^(8a), R^(8a2), R^(8a4), and R^(8a5) are independently H,alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,(heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R¹², —CO₂R¹²,—C(O)—NR¹²R¹³, or —NR¹²R¹³ any of which may be optionally independentlysubstituted with one or more groups T^(1d), T^(2d) or T^(3d); or R⁶ andR⁷, together with the nitrogen atom to which they are attached maycombine to form a saturated or unsaturated 4 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); or one of R⁶ or R⁷, may combine with one of R⁸ orR^(8a) to form a saturated or unsaturated 5 to 8 membered ringoptionally independently substituted with one or more groups T^(1d),T^(2b) or T^(3d); (t) R^(6a) is H; (u) R^(7a) is heteroaryl, which maybe optionally independently substituted with one or more groups T^(1d),T^(2d) or T^(3d); (v) R^(8b) is independently H, alkyl, aryl, cyano,nitro, acyl or —SO₂(alkyl); (w) R^(8c) is independently H, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl,heteroaryl, amino or alkoxy; (x) R^(8d) is R⁴, COR⁴, CO₂R⁴, SO₂R⁴,CONR⁶R⁷, or SO₂—NR⁶R⁷; (y) R^(12 a) nd R^(13 a) are independently H,alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any ofwhich may be optionally independently substituted with one or moregroups T^(1f), T^(2f) or T^(3f) or R^(12 a) nd R¹³ together with thenitrogen atom to which they are attached may combine to form a saturatedor unsaturated ring which may be optionally independently substitutedwith one or more groups T^(1f), T^(2f) or T^(3f); (z) W is ═NR^(8a2),═N—CO₂R^(8a2), ═N—COR^(8a2), ═N—CN, or ═N—SO₂R^(8a2); (aa) Z and Z² areindependently ═O, ═S, ═NR^(8a4) or ═N—CN; (bb) R¹⁴ is independently

 where q is 1, 2 or 3; R^(Y) is an optional oxo substituent attached toany available ring carbon atom; X¹ is O, S, NR^(8a5) or CH₂; and X² isNR^(8a5) or CH₂; (cc) X² is one or more optional substituents, attachedto any available ring carbon atom, independently selected from T^(1g),T^(2g)or T^(3g); (dd) T^(1-1g), T^(2-2g) or T^(3-3g) are eachindependently (1) hydrogen or T⁶, where T⁶ is (i) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,clycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i)which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more (preferably 1 to 3) of the following groups(2) to (13) of the definition of T^(1-1g), T^(2-2g) and T^(3-3g); (2)—OH or —OT⁶, (3) —SH or —ST⁶, (4) —C(O)_(t)H, —C(O)_(t)T⁶, or —O—C(O)T⁶,where t is 1 or 2; (5) —SO₃H, —S(O)_(t)T⁶, or S(O)_(t)N(T⁹)T⁶, (6) halo,(7) cyano, (8) nitro, (9) -T⁴-NT⁷T⁸, (10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸, (11)-T⁴-N(T¹⁰)-T⁵-T⁶, (12) -T⁴-N(T¹⁰)-T⁵-H, (13) oxo, (ee) T⁴ and T⁵ areeach independently (1) a single bond, (2) -T¹¹-S(O)_(t)-T¹²-, (3)-T¹¹-C(O)-T¹²-, (4) -T¹¹-(S)-T¹²-, (5) -T¹¹-O-T¹²-, (6) -T¹¹-S-T¹²-, (7)-T¹¹-O—C(O)-T¹²-, (8) -T¹¹-C(O)—O-T¹²-, (9) -T¹¹-C(═NT^(9a))-T¹²-, or(10) -T¹¹-C(O)—C(O)-T¹²-, (ff) T⁷, T⁸, T⁹, T⁹ and T¹⁰ (¹) are eachindependently hydrogen or a group provided in the definition of T⁶, or(2) T⁷ and T⁸ may together be alkylene or alkenylene, completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached, which ring is unsubstituted or substituted withone or more groups listed in the definition of T^(1-1g), T^(2-2g) andT^(3-3g), or (3) T⁷ or T⁸, together with T⁹, may be alkylene oralkenylene completing a 3- to 8-membered saturated or unsaturated ringtogether with the nitrogen atoms to which they are attached, which ringis unsubstituted or substituted with one or more groups listed in thedefinition of T^(1-1g), T^(2-2g) and T^(3-3g), or (4) T⁷ and T⁸ or T⁹and T¹⁰ together with the nitrogen atom to which they are attached maycombine to form a group —N═CT¹³T¹⁴ where T¹³ and T¹⁴ are eachindependently H or a group provided in the definition of T⁶; (gg) T¹¹and T¹² are each independently (1) a single bond, (2) alkylene, (3)alkenylene, or (4) alkynylene.